diff --git a/java/src/org/broadinstitute/sting/gatk/executive/MicroScheduler.java b/java/src/org/broadinstitute/sting/gatk/executive/MicroScheduler.java
index ce5507386..029ad0c4e 100755
--- a/java/src/org/broadinstitute/sting/gatk/executive/MicroScheduler.java
+++ b/java/src/org/broadinstitute/sting/gatk/executive/MicroScheduler.java
@@ -26,6 +26,9 @@
 package org.broadinstitute.sting.gatk.executive;
 
 import net.sf.picard.reference.ReferenceSequenceFile;
+import net.sf.samtools.SAMFileHeader;
+import net.sf.samtools.SAMSequenceDictionary;
+import net.sf.samtools.SAMSequenceRecord;
 import org.apache.log4j.Logger;
 import org.broadinstitute.sting.gatk.Reads;
 import org.broadinstitute.sting.gatk.datasources.providers.ShardDataProvider;
@@ -41,12 +44,12 @@ import org.broadinstitute.sting.gatk.walkers.*;
 import org.broadinstitute.sting.utils.GenomeLocParser;
 import org.broadinstitute.sting.utils.GenomeLocSortedSet;
 import org.broadinstitute.sting.utils.StingException;
+import org.broadinstitute.sting.utils.Utils;
 import org.broadinstitute.sting.utils.fasta.IndexedFastaSequenceFile;
 
 import java.io.File;
 import java.io.FileNotFoundException;
-import java.util.ArrayList;
-import java.util.List;
+import java.util.*;
 
 
 /**
@@ -114,6 +117,8 @@ public abstract class MicroScheduler {
         this.reads = getReadsDataSource(reads);
         this.reference = openReferenceSequenceFile(refFile);
         this.rods = getReferenceOrderedDataSources(rods);
+
+        validate(this.reads,this.reference);
     }
 
     /**
@@ -277,4 +282,62 @@ public abstract class MicroScheduler {
         GenomeLocParser.setupRefContigOrdering(ref);
         return ref;
     }
+
+    /**
+     * Now that all files are open, validate the sequence dictionaries of the reads vs. the reference.
+     * TODO: Doing this in the MicroScheduler is a bit late, but this is where data sources are initialized.
+     * TODO: Move the initialization of data sources back to the GenomeAnalysisEngine.
+     * @param reads Reads data source.
+     * @param reference Reference data source.
+     */
+    private void validate( SAMDataSource reads, ReferenceSequenceFile reference ) {
+        if( reads == null || reference == null )
+            return;
+        
+        // Compile a set of sequence names that exist in the BAM files.
+        SAMSequenceDictionary readsDictionary = reads.getHeader().getSequenceDictionary();
+
+        Set<String> readsSequenceNames = new TreeSet<String>();
+        for( SAMSequenceRecord dictionaryEntry: readsDictionary.getSequences() )
+            readsSequenceNames.add(dictionaryEntry.getSequenceName());
+
+        // Compile a set of sequence names that exist in the reference file.
+        SAMSequenceDictionary referenceDictionary = reference.getSequenceDictionary();
+
+        Set<String> referenceSequenceNames = new TreeSet<String>();
+        for( SAMSequenceRecord dictionaryEntry: referenceDictionary.getSequences() )
+            referenceSequenceNames.add(dictionaryEntry.getSequenceName());
+
+        // If there's no overlap between reads and reference, data will be bogus.  Throw an exception.
+        Set<String> intersectingSequenceNames = new HashSet<String>(readsSequenceNames);
+        intersectingSequenceNames.retainAll(referenceSequenceNames);
+        if( intersectingSequenceNames.size() == 0 ) {
+            StringBuilder error = new StringBuilder();
+            error.append("No overlap exists between sequence dictionary of the reads and the sequence dictionary of the reference.  Perhaps you're using the wrong reference?\n");
+            error.append(System.getProperty("line.separator"));
+            error.append(String.format("Reads contigs:     %s%n", prettyPrintSequenceRecords(readsDictionary)));
+            error.append(String.format("Reference contigs: %s%n", prettyPrintSequenceRecords(referenceDictionary)));
+            logger.error(error.toString());
+            Utils.scareUser("No overlap exists between sequence dictionary of the reads and the sequence dictionary of the reference.");
+        }
+
+        // If one data source isn't a strict subset of the other or the match is of fewer than x% of the smaller,
+        // issue a warning.
+        if( !readsSequenceNames.equals(referenceSequenceNames) ) {
+            StringBuilder warning = new StringBuilder();
+            warning.append("Limited overlap exists between sequence dictionary of the reads and the sequence dictionary of the reference.  Perhaps you're using the wrong reference?\n");
+            warning.append(System.getProperty("line.separator"));
+            warning.append(String.format("Reads contigs:     %s%n", prettyPrintSequenceRecords(readsDictionary)));
+            warning.append(String.format("Reference contigs: %s%n", prettyPrintSequenceRecords(referenceDictionary)));
+            logger.warn(warning.toString());
+        }
+    }
+
+    private String prettyPrintSequenceRecords( SAMSequenceDictionary sequenceDictionary ) {
+        String[] sequenceRecordNames = new String[ sequenceDictionary.size() ];
+        int sequenceRecordIndex = 0;
+        for( SAMSequenceRecord sequenceRecord: sequenceDictionary.getSequences() )
+            sequenceRecordNames[sequenceRecordIndex++] = sequenceRecord.getSequenceName();
+        return Arrays.deepToString(sequenceRecordNames);
+    }
 }
diff --git a/java/src/org/broadinstitute/sting/utils/Utils.java b/java/src/org/broadinstitute/sting/utils/Utils.java
index a924e4d3c..66817cb2c 100755
--- a/java/src/org/broadinstitute/sting/utils/Utils.java
+++ b/java/src/org/broadinstitute/sting/utils/Utils.java
@@ -40,7 +40,7 @@ public class Utils {
         //System.out.printf("* %s%n", msg);
         //System.out.printf("********************************************************************************%n");
         logger.fatal(msg);
-        throw new RuntimeException(msg);
+        throw new StingException(msg);
     }
 
     public static <T> List<T> cons(final T elt, final List<T> l) {