The hippocampus and the basal ganglia are thought to play fundamental and distinct roles in learning and memory, supporting two dissociable memory systems. Interestingly, however, the hippocampus and the basal ganglia have each, separately, been implicated as necessary for reversal learning—the ability to adaptively change a response when previously learned stimulus–outcome contingencies are reversed. Here, we compared the contribution of the hippocampus and the basal ganglia to distinct aspects of learning and reversal. Amnesic subjects with selective hippocampal damage, Parkinson subjects with disrupted basal ganglia function, and healthy controls were tested on a novel probabilistic learning and reversal paradigm. In this task, reversal can be achieved in two ways: Subjects can reverse a previously learned response, or they can select a new cue during the reversal phase, effectively “opting out” of the reversal. We found that both patient groups were intact at initial learning, but differed in their ability to reverse. Amnesic subjects failed to reverse, and continued to use the same cue and response learned before the reversal. Parkinson subjects, by contrast, opted out of the reversal by learning a new cue–outcome association. These results suggest that both the hippocampus and the basal ganglia support reversal learning, but in different ways. The basal ganglia are necessary for learning a new response when a previously learned response is no longer rewarding. The failure of the amnesic subjects to reverse their response or to learn a new cue is consistent with a more general role for the hippocampus in configural learning, and suggests it may also support the ability to respond to changes in cue–outcome contingencies.