diff --git a/tasks/src/main/scala/dagr/tasks/gatk/GatkTask.scala b/tasks/src/main/scala/dagr/tasks/gatk/GatkTask.scala
index 16b75316..de9a3a09 100644
--- a/tasks/src/main/scala/dagr/tasks/gatk/GatkTask.scala
+++ b/tasks/src/main/scala/dagr/tasks/gatk/GatkTask.scala
@@ -23,18 +23,48 @@
  */
 package dagr.tasks.gatk
 
-import java.nio.file.Path
+import java.nio.file.{Files, Path}
+import java.util.jar.Attributes.Name
+import java.util.jar.JarInputStream
 
 import dagr.core.config.Configuration
 import dagr.core.execsystem.{Cores, Memory}
 import dagr.core.tasksystem.{FixedResources, ProcessTask}
-import dagr.tasks.{DagrDef, JarTask}
-import DagrDef.{PathToFasta, PathToIntervals}
+import dagr.tasks.JarTask
+import com.fulcrumgenomics.commons.CommonsDef._
 
 import scala.collection.mutable.ListBuffer
 
 object GatkTask {
+  /** The config path to the primary GATK Jar. */
   val GatkJarPathConfigKey = "gatk.jar"
+
+  private[gatk] val ImplementationVersion = new Name("Implementation-Version")
+  private[gatk] val MainClass             = new Name("Main-Class")
+
+  /** Attempts to determine the major version from the GATK Jar. */
+  def majorVersion(jar: FilePath): Int = {
+    val in    = new JarInputStream(Files.newInputStream(jar))
+    val attrs = in.getManifest.getMainAttributes
+    in.close()
+
+    if (attrs.containsKey(ImplementationVersion)) {
+      attrs.getValue(ImplementationVersion).takeWhile(_ != '.').toInt
+    }
+    else {
+      attrs.getValue(MainClass) match {
+        case "org.broadinstitute.sting.gatk.CommandLineGATK"  => 1
+        case "org.broadinstitute.gatk.engine.CommandLineGATK" => 3
+        case x => throw new IllegalArgumentException(s"Couldn't determine GATK version from jar $jar")
+      }
+    }
+  }
+
+  /** The path to the "standard" GATK jar. */
+  lazy val GatkJarPath: FilePath = Configuration.configure[Path](GatkTask.GatkJarPathConfigKey)
+
+  /** The major version of the "standard" GATK jar. */
+  lazy val GatkMajorVersion: Int = majorVersion(GatkJarPath)
 }
 
 
@@ -49,12 +79,18 @@ abstract class GatkTask(val walker: String,
   requires(Cores(1), Memory("4g"))
 
   override def args: Seq[Any] = {
-    val buffer = ListBuffer[Any]()
-    buffer.appendAll(jarArgs(this.gatkJar, jvmMemory=this.resources.memory))
-    buffer.append("-T", this.walker)
+    val buffer  = ListBuffer[Any]()
+    val jvmArgs = if (gatkMajorVersion >= 4) bamCompression.map(c => s"-Dsamjdk.compression_level=$c") else None
+    buffer.appendAll(jarArgs(this.gatkJar, jvmMemory=this.resources.memory, jvmArgs=jvmArgs))
+
+    if (gatkMajorVersion < 4) buffer += "-T"
+    buffer += this.walker
+
+    if (gatkMajorVersion < 4) bamCompression.foreach(c => buffer.append("--bam_compression", c))
+
     buffer.append("-R", this.ref.toAbsolutePath.toString)
     intervals.foreach(il => buffer.append("-L", il.toAbsolutePath.toString))
-    bamCompression.foreach(c => buffer.append("--bam_compression", c))
+
     addWalkerArgs(buffer)
     buffer.toSeq
   }
@@ -62,5 +98,13 @@ abstract class GatkTask(val walker: String,
   /** Can be overridden to use a specific GATK jar. */
   protected def gatkJar: Path = configure[Path](GatkTask.GatkJarPathConfigKey)
 
+  /** The version of GATK being used by this task. */
+  protected lazy val gatkMajorVersion: Int = {
+    val jar = gatkJar
+    if (jar == GatkTask.GatkJarPath) GatkTask.GatkMajorVersion
+    else GatkTask.majorVersion(jar)
+  }
+
+  /** Adds arguments specific to the walker. */
   protected def addWalkerArgs(buffer: ListBuffer[Any]): Unit
 }
diff --git a/tasks/src/main/scala/dagr/tasks/gatk/GenotypeGvcfs.scala b/tasks/src/main/scala/dagr/tasks/gatk/GenotypeGvcfs.scala
index d675690b..366e3fbd 100644
--- a/tasks/src/main/scala/dagr/tasks/gatk/GenotypeGvcfs.scala
+++ b/tasks/src/main/scala/dagr/tasks/gatk/GenotypeGvcfs.scala
@@ -50,9 +50,18 @@ class GenotypeGvcfs private (ref: PathToFasta,
                              val dbSnpVcf: Option[PathToVcf] = None)
   extends GatkTask("GenotypeGVCFs", ref, intervals=intervals) {
 
+  require(gvcfs.length == 1 || gatkMajorVersion < 4, "GenotypeGVCFs only supports one GVCF at a time with GATK version 4+.")
+
   override protected def addWalkerArgs(buffer: ListBuffer[Any]): Unit = {
-    dbSnpVcf.foreach(v => buffer.append("--dbsnp", v.toAbsolutePath.toString))
-    gvcfs.foreach(gvcf => buffer.append("-V", gvcf.toAbsolutePath.toString))
-    buffer.append("-o", vcf.toAbsolutePath.toString)
+    // Args that are common to all versions
+    dbSnpVcf.foreach(v => buffer.append("--dbsnp", v.toAbsolutePath))
+    gvcfs.foreach(gvcf => buffer.append("-V", gvcf.toAbsolutePath))
+
+    gatkMajorVersion match {
+      case n if n < 4  =>
+        buffer.append("--out", vcf.toAbsolutePath)
+      case n if n >= 4 =>
+        buffer.append("--output", vcf.toAbsolutePath)
+    }
   }
 }
diff --git a/tasks/src/main/scala/dagr/tasks/gatk/HaplotypeCaller.scala b/tasks/src/main/scala/dagr/tasks/gatk/HaplotypeCaller.scala
index e20c2367..f04cb5b7 100644
--- a/tasks/src/main/scala/dagr/tasks/gatk/HaplotypeCaller.scala
+++ b/tasks/src/main/scala/dagr/tasks/gatk/HaplotypeCaller.scala
@@ -36,6 +36,7 @@ class HaplotypeCaller(ref: PathToFasta,
                       val bam: PathToBam,
                       val vcf: PathToVcf,
                       val maxAlternateAlleles: Int = 3,
+                      val maxHaplotypes: Int = 200,
                       val minPruning: Int = 3,
                       val contaminationFraction: Double = 0.0,
                       val rnaMode: Boolean = false,
@@ -47,25 +48,47 @@ class HaplotypeCaller(ref: PathToFasta,
  extends GatkTask("HaplotypeCaller", ref, intervals=intervals) {
 
   override protected def addWalkerArgs(buffer: ListBuffer[Any]): Unit = {
-    buffer.append("--minPruning", minPruning)
-    buffer.append("--maxNumHaplotypesInPopulation", "200")
-    buffer.append("-variant_index_parameter", "128000")
-    buffer.append("-variant_index_type", "LINEAR")
-    buffer.append("--emitRefConfidence", "GVCF")
-    ploidy.foreach(p => buffer.append("--sample_ploidy", p))
-    buffer.append("--max_alternate_alleles", maxAlternateAlleles)
-    maxReadsInRegionPerSample.foreach(n => buffer.append("--maxReadsInRegionPerSample", n))
-    minReadsPerAlignmentStart.foreach(n => buffer.append("--minReadsPerAlignmentStart", n))
-    buffer.append("--contamination_fraction_to_filter", contaminationFraction)
+    // Args common between versions
     buffer.append("-I", bam.toAbsolutePath)
-    buffer.append("-o", vcf.toAbsolutePath)
 
-    if (rnaMode) {
-      buffer.append("-dontUseSoftClippedBases")
-      buffer.append("-stand_call_conf", 20)
-      buffer.append("-stand_emit_conf", 20)
-    }
+    gatkMajorVersion match {
+      case n if n <  4 =>
+        // Args for versions 1-3
+        buffer.append("-o", vcf.toAbsolutePath)
+        buffer.append("--minPruning", minPruning)
+        buffer.append("--maxNumHaplotypesInPopulation", maxHaplotypes)
+        buffer.append("--emitRefConfidence", "GVCF")
+        buffer.append("--max_alternate_alleles", maxAlternateAlleles)
+        buffer.append("--contamination_fraction_to_filter", contaminationFraction)
+        ploidy.foreach(p => buffer.append("--sample_ploidy", p))
+        if (useNativePairHmm) buffer.append("-pairHMM", "VECTOR_LOGLESS_CACHING")
+
+        buffer.append("-variant_index_parameter", "128000")
+        buffer.append("-variant_index_type", "LINEAR")
+        maxReadsInRegionPerSample.foreach(n => buffer.append("--maxReadsInRegionPerSample", n))
+        minReadsPerAlignmentStart.foreach(n => buffer.append("--minReadsPerAlignmentStart", n))
+
+        if (rnaMode) {
+          buffer.append("-dontUseSoftClippedBases")
+          buffer.append("-stand_call_conf", 20)
+          buffer.append("-stand_emit_conf", 20)
+        }
 
-    if (useNativePairHmm) buffer.append("-pairHMM", "VECTOR_LOGLESS_CACHING")
+      case n if n >= 4 =>
+        // Args for version 4
+        buffer.append("-O", vcf.toAbsolutePath)
+        buffer.append("--min-pruning", minPruning)
+        buffer.append("--max-num-haplotypes-in-population", "200")
+        buffer.append("--emit-ref-confidence", "GVCF")
+        buffer.append("--max-alternate-alleles", maxAlternateAlleles)
+        buffer.append("--contamination-fraction-to-filter", contaminationFraction)
+        ploidy.foreach(p => buffer.append("--sample-ploidy", p))
+        if (useNativePairHmm) buffer.append("-pairHMM", "FASTEST_AVAILABLE")
+
+        if (rnaMode) {
+          buffer.append("--dont-use-soft-clipped-bases")
+          buffer.append("-stand-call-conf", 20)
+        }
+    }
   }
 }
diff --git a/tasks/src/main/scala/dagr/tasks/gatk/IndelRealigner.scala b/tasks/src/main/scala/dagr/tasks/gatk/IndelRealigner.scala
index 4706b9b1..4b251b3f 100644
--- a/tasks/src/main/scala/dagr/tasks/gatk/IndelRealigner.scala
+++ b/tasks/src/main/scala/dagr/tasks/gatk/IndelRealigner.scala
@@ -95,6 +95,7 @@ class RealignerTargetCreator(val in: Seq[PathToBam],
                              intervals: Option[PathToIntervals])
   extends GatkTask(walker = "RealignerTargetCreator", ref = ref, intervals = intervals) {
 
+  require(gatkMajorVersion < 4, s"RealignerTargetCreator is not supported in GATK v$gatkMajorVersion.")
   override protected def addWalkerArgs(buffer: ListBuffer[Any]): Unit = {
     in.foreach(bam => buffer.append("-I", bam))
     buffer.append("-o", out)
@@ -111,6 +112,8 @@ class IndelRealigner(val in: Seq[PathToBam],
                      bamCompression: Option[Int] = None)
   extends GatkTask(walker = "IndelRealigner", ref = ref, bamCompression = bamCompression) {
 
+  require(gatkMajorVersion < 4, s"IndelRealigner is not supported in GATK v$gatkMajorVersion.")
+
   override protected def addWalkerArgs(buffer: ListBuffer[Any]): Unit = {
     in.foreach(bam => buffer.append("-I", bam))
     known.foreach(vcf => buffer.append("-known", vcf))
diff --git a/tasks/src/main/scala/dagr/tasks/gatk/Mutect1.scala b/tasks/src/main/scala/dagr/tasks/gatk/Mutect1.scala
index 055365f6..cf6c0751 100644
--- a/tasks/src/main/scala/dagr/tasks/gatk/Mutect1.scala
+++ b/tasks/src/main/scala/dagr/tasks/gatk/Mutect1.scala
@@ -50,6 +50,8 @@ class Mutect1(val tumorBam: PathToBam,
               val minBaseQuality: Int = 5
              ) extends GatkTask(walker="MuTect", ref=ref, intervals=Some(intervals)) {
 
+  require(gatkMajorVersion < 4, s"Mutect v1 is not supported in GATK v${gatkMajorVersion}.")
+
   override protected def addWalkerArgs(buffer: ListBuffer[Any]): Unit = {
     buffer.append("-o",   callStatsOutput)
     buffer.append("-vcf", vcfOutput)
diff --git a/tasks/src/main/scala/dagr/tasks/gatk/Mutect2.scala b/tasks/src/main/scala/dagr/tasks/gatk/Mutect2.scala
index 61c5f446..cfece3e5 100644
--- a/tasks/src/main/scala/dagr/tasks/gatk/Mutect2.scala
+++ b/tasks/src/main/scala/dagr/tasks/gatk/Mutect2.scala
@@ -24,8 +24,8 @@
 package dagr.tasks.gatk
 
 import dagr.core.tasksystem.FixedResources
-import dagr.tasks.DagrDef
-import DagrDef.{PathToBam, PathToFasta, PathToIntervals, PathToVcf}
+import com.fulcrumgenomics.commons.CommonsDef._
+import htsjdk.samtools.SamReaderFactory
 
 import scala.collection.mutable.ListBuffer
 
@@ -43,11 +43,28 @@ class Mutect2(val tumorBam: PathToBam,
              ) extends GatkTask(walker="MuTect2", ref=ref, intervals=Some(intervals)) with FixedResources {
 
   override protected def addWalkerArgs(buffer: ListBuffer[Any]): Unit = {
-    buffer.append("-I:tumor",  tumorBam)
-    buffer.append("-I:normal", normalBam)
-    buffer.append("-o", output)
-    buffer.append("--max_alt_allele_in_normal_fraction",    maxAltAlleleInNormalFraction)
-    buffer.append("--max_alt_alleles_in_normal_count",      maxAltAlleleInNormalCount)
-    buffer.append("--max_alt_alleles_in_normal_qscore_sum", maxAltAlleleInNormalBqSum)
+    gatkMajorVersion match {
+      case n if n < 4 =>
+        buffer.append("-I:tumor",  tumorBam)
+        buffer.append("-I:normal", normalBam)
+        buffer.append("-o", output)
+        buffer.append("--max_alt_allele_in_normal_fraction",    maxAltAlleleInNormalFraction)
+        buffer.append("--max_alt_alleles_in_normal_count",      maxAltAlleleInNormalCount)
+        buffer.append("--max_alt_alleles_in_normal_qscore_sum", maxAltAlleleInNormalBqSum)
+      case n if n >= 4 =>
+        buffer.append("-I", tumorBam)
+        buffer.append("-I", normalBam)
+        sampleNames(normalBam).foreach { n => buffer.append("--normal-sample", n) }
+        buffer.append("-O", output)
+    }
+  }
+
+  /** Gets the unique set of samples names in the RG headers of a BAM. */
+  private def sampleNames(bam: PathToBam): Seq[String] = {
+    val in = SamReaderFactory.make().open(bam)
+    val rgs = in.getFileHeader.getReadGroups
+    in.close()
+
+    rgs.flatMap(rg => Option(rg.getSample)).toIndexedSeq.distinct
   }
 }
diff --git a/tasks/src/main/scala/dagr/tasks/gatk/SplitNCigarReads.scala b/tasks/src/main/scala/dagr/tasks/gatk/SplitNCigarReads.scala
index 6ac5d0f1..31af3adb 100644
--- a/tasks/src/main/scala/dagr/tasks/gatk/SplitNCigarReads.scala
+++ b/tasks/src/main/scala/dagr/tasks/gatk/SplitNCigarReads.scala
@@ -37,7 +37,13 @@ class SplitNCigarReads(val in: PathToBam, val out: PathToBam, ref:PathToFasta, b
 
   override protected def addWalkerArgs(buffer: ListBuffer[Any]): Unit = {
     buffer.append("-I", in)
-    buffer.append("-o", out)
-    buffer.append("-U", "ALLOW_N_CIGAR_READS")
+
+    gatkMajorVersion match {
+      case n if n < 4 =>
+        buffer.append("-o", out)
+        buffer.append("-U", "ALLOW_N_CIGAR_READS")
+      case n if n >= 4 =>
+        buffer.append("-O", out)
+    }
   }
 }