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We examined interactions between frontal, striatal, and hippocampal systems during a rule-learning task. Nineteen healthy young adults solved multiple rule-learning problems requiring hypothesis testing while functional magnetic resonance images were obtained. Activity in the head of the caudate peaked early after the beginning of each problem and then dropped rapidly. In contrast, activity in prefrontal cortex areas reached peak values later. These results are in accordance with theories suggesting that the striatum identifies the behavioral context necessary for the frontal lobe to select an appropriate strategy. Striatal and hippocampal systems showed antagonistic patterns of activity: Activation in the anterior hippocampus decreased, whereas caudate activity increased. Good learners showed higher activity in the body and tail of the caudate than poor learners, whereas learning success correlated negatively with activity in the hippocampus. Activation in the head of the caudate correlated negatively with hippocampal activation, indicating a potential mechanism for hippocampal activity reduction.