How do the frontal lobes support behavioural flexibility? One key element is the ability to adjust responses when the reinforcement value of stimuli change. In monkeys, this ability--a form of affective shifting known as reversal learning--depends on orbitofrontal cortex. The present study examines the anatomical bases of reversal learning in humans. Subjects with lesions of the ventromedial prefrontal cortex were compared with a group with dorsolateral frontal lobe damage, as well as with normal controls on a simple reversal learning task. Neither form of frontal damage affected initial stimulus-reinforcement learning; ventromedial frontal damage selectively impaired reversal learning.