diff --git a/java/src/org/broadinstitute/sting/utils/cmdLine/Argument.java b/java/src/org/broadinstitute/sting/utils/cmdLine/Argument.java
index 5e951167f..454fc8d56 100755
--- a/java/src/org/broadinstitute/sting/utils/cmdLine/Argument.java
+++ b/java/src/org/broadinstitute/sting/utils/cmdLine/Argument.java
@@ -58,5 +58,5 @@ public @interface Argument {
      * @return A comma-separated string listing other arguments of which this
      *         argument should be independent.
      */
-    String exclusive() default "";
+    String exclusiveOf() default "";
 }
diff --git a/java/src/org/broadinstitute/sting/utils/cmdLine/ArgumentDefinitions.java b/java/src/org/broadinstitute/sting/utils/cmdLine/ArgumentDefinitions.java
index bd36dc604..545c1caa4 100755
--- a/java/src/org/broadinstitute/sting/utils/cmdLine/ArgumentDefinitions.java
+++ b/java/src/org/broadinstitute/sting/utils/cmdLine/ArgumentDefinitions.java
@@ -237,7 +237,7 @@ class ArgumentDefinition {
     /**
      * Is this argument exclusive of other arguments?
      */
-    public final String exclusive;
+    public final String exclusiveOf;
 
     public final Class sourceClass;
     public final Field sourceField;
@@ -256,7 +256,7 @@ class ArgumentDefinition {
         shortName = argument.shortName().trim().length() > 0 ? argument.shortName().trim() : null;
         doc = argument.doc();
         required = argument.required() && !isFlag();
-        exclusive = argument.exclusive().trim().length() > 0 ? argument.exclusive().trim() : null;
+        exclusiveOf = argument.exclusiveOf().trim().length() > 0 ? argument.exclusiveOf().trim() : null;
     }
 
     /**
diff --git a/java/src/org/broadinstitute/sting/utils/cmdLine/ArgumentMatches.java b/java/src/org/broadinstitute/sting/utils/cmdLine/ArgumentMatches.java
index d45d1e64d..c3c3892b0 100755
--- a/java/src/org/broadinstitute/sting/utils/cmdLine/ArgumentMatches.java
+++ b/java/src/org/broadinstitute/sting/utils/cmdLine/ArgumentMatches.java
@@ -120,6 +120,17 @@ public class ArgumentMatches implements Iterable<ArgumentMatch> {
         return matches;
     }
 
+    /**
+     * Find all successful matches (a 'successful' match is one paired with a definition).
+     */
+    public Collection<ArgumentMatch> findSuccessfulMatches() {
+        Collection<ArgumentMatch> matches = new HashSet<ArgumentMatch>();
+        for( ArgumentMatch argumentMatch: getUniqueMatches() ) {
+            if( argumentMatch.definition != null )
+                matches.add( argumentMatch );
+        }
+        return matches;
+    }
 }
 
 /**
diff --git a/java/src/org/broadinstitute/sting/utils/cmdLine/ParsingEngine.java b/java/src/org/broadinstitute/sting/utils/cmdLine/ParsingEngine.java
index 36c82b53d..09c511f1f 100755
--- a/java/src/org/broadinstitute/sting/utils/cmdLine/ParsingEngine.java
+++ b/java/src/org/broadinstitute/sting/utils/cmdLine/ParsingEngine.java
@@ -1,6 +1,7 @@
 package org.broadinstitute.sting.utils.cmdLine;
 
 import org.broadinstitute.sting.utils.StingException;
+import org.broadinstitute.sting.utils.Pair;
 import org.apache.log4j.Logger;
 
 import java.lang.reflect.Field;
@@ -112,7 +113,8 @@ public class ParsingEngine {
     public enum ValidationType { MissingRequiredArgument,
                                  InvalidArgument,
                                  ValueMissingArgument,
-                                 TooManyValuesForArgument };
+                                 TooManyValuesForArgument,
+                                 MutuallyExclusive };
 
     /**
      * Validates the list of command-line argument matches.
@@ -157,17 +159,35 @@ public class ParsingEngine {
         // Find arguments with too many values.
         if( !skipValidationOf.contains(ValidationType.TooManyValuesForArgument)) {
             Collection<ArgumentMatch> overvaluedArguments = new ArrayList<ArgumentMatch>();
-            for( ArgumentMatch argumentMatch: argumentMatches ) {
+            for( ArgumentMatch argumentMatch: argumentMatches.findSuccessfulMatches() ) {
                 // Warning: assumes that definition is not null (asserted by checks above).
-                if( argumentMatch.definition != null &&
-                        !argumentMatch.definition.isMultiValued() &&
-                        argumentMatch.values().size() > 1 )
+                if( !argumentMatch.definition.isMultiValued() && argumentMatch.values().size() > 1 )
                     overvaluedArguments.add(argumentMatch);
             }
 
             if( !overvaluedArguments.isEmpty() )
                 throw new TooManyValuesForArgumentException(overvaluedArguments);
         }
+
+        // Find sets of options that are supposed to be mutually exclusive.
+        if( !skipValidationOf.contains(ValidationType.MutuallyExclusive)) {
+            Collection<Pair<ArgumentMatch,ArgumentMatch>> invalidPairs = new ArrayList<Pair<ArgumentMatch,ArgumentMatch>>();
+            for( ArgumentMatch argumentMatch: argumentMatches.findSuccessfulMatches() ) {
+                if( argumentMatch.definition.exclusiveOf != null ) {
+                    for( ArgumentMatch conflictingMatch: argumentMatches.findSuccessfulMatches() ) {
+                        // Skip over the current element.
+                        if( argumentMatch == conflictingMatch )
+                            continue;
+                        if( argumentMatch.definition.exclusiveOf.equals(conflictingMatch.definition.fullName) ||
+                            argumentMatch.definition.exclusiveOf.equals(conflictingMatch.definition.shortName))
+                            invalidPairs.add( new Pair<ArgumentMatch,ArgumentMatch>(argumentMatch, conflictingMatch) );
+                    }
+                }
+            }
+
+            if( !invalidPairs.isEmpty() )
+                throw new ArgumentsAreMutuallyExclusiveException( invalidPairs );
+        }
     }
 
     /**
@@ -537,7 +557,24 @@ class TooManyValuesForArgumentException extends ParseException {
     private static String formatArguments( Collection<ArgumentMatch> arguments ) {
         StringBuilder sb = new StringBuilder();
         for( ArgumentMatch argument: arguments )
-            sb.append( String.format("Argument with name '%s' has to many values: %s", argument.label, Arrays.deepToString(argument.values().toArray())) );
+            sb.append( String.format("Argument '%s' has to many values: %s", argument.label, Arrays.deepToString(argument.values().toArray())) );
         return sb.toString();
     }
+}
+
+/**
+ * An exception indicating that mutually exclusive options have been passed in the same command line.
+ */
+class ArgumentsAreMutuallyExclusiveException extends ParseException {
+    public ArgumentsAreMutuallyExclusiveException( Collection<Pair<ArgumentMatch,ArgumentMatch>> arguments ) {
+        super( formatArguments(arguments) );
+    }
+
+    private static String formatArguments( Collection<Pair<ArgumentMatch,ArgumentMatch>> arguments ) {
+        StringBuilder sb = new StringBuilder();
+        for( Pair<ArgumentMatch,ArgumentMatch> argument: arguments )
+            sb.append( String.format("Arguments '%s' and '%s' are mutually exclusive.", argument.first.definition.fullName, argument.second.definition.fullName ) );
+        return sb.toString();
+    }
+
 }
\ No newline at end of file
diff --git a/java/test/org/broadinstitute/sting/utils/cmdLine/ParsingEngineTest.java b/java/test/org/broadinstitute/sting/utils/cmdLine/ParsingEngineTest.java
index 0618763dd..ef9c87f07 100755
--- a/java/test/org/broadinstitute/sting/utils/cmdLine/ParsingEngineTest.java
+++ b/java/test/org/broadinstitute/sting/utils/cmdLine/ParsingEngineTest.java
@@ -425,4 +425,32 @@ public class ParsingEngineTest extends BaseTest {
         parsingEngine.validate( EnumSet.of(ParsingEngine.ValidationType.MissingRequiredArgument) );
     }
 
+    @Test(expected=ArgumentsAreMutuallyExclusiveException.class)
+    public void testMutuallyExclusiveArguments() {
+        // Passing only foo should work fine...
+        String[] commandLine = new String[] {"--foo","5"};
+
+        parsingEngine.addArgumentSource( MutuallyExclusiveArgProvider.class );
+        parsingEngine.parse( commandLine );
+        parsingEngine.validate();
+
+        MutuallyExclusiveArgProvider argProvider = new MutuallyExclusiveArgProvider();
+        parsingEngine.loadArgumentsIntoObject( argProvider );
+
+        Assert.assertEquals("Argument is not correctly initialized", 5, argProvider.foo.intValue() );
+
+        // But when foo and bar come together, danger!
+        commandLine = new String[] {"--foo","5","--bar","6"};
+
+        parsingEngine.parse( commandLine );
+        parsingEngine.validate();        
+    }
+
+    private class MutuallyExclusiveArgProvider {
+        @Argument(doc="foo",exclusiveOf="bar")
+        Integer foo;
+
+        @Argument(doc="bar",required=false)
+        Integer bar;
+    }
 }