According to dual-system accounts, instrumental learning is supported by both a goal-directed and a habitual system. Although behavioral control by the goal-directed system, through outcome–action associations, dominates with moderate training, stimulus–response associations are thought to form concurrently in the habit system. It is therefore challenging to isolate the neural substrate of the goal-directed system in neuroimaging research with healthy human volunteers. Recently, however, developed an instrumental discrimination task that distinguishes between goal-directed and habit-based responding. In this task, cues are congruent, unrelated, or incongruent with subsequent outcomes. Whereas performance on congruent and control trials can be supported by both the goal-directed and habitual system, performance on the incongruent discrimination relies solely on the habit system. In the present study, we used this task with healthy participants undergoing functional magnetic resonance imaging to demonstrate that engagement of the goal-directed system during learning is reflected in increased activity in the ventromedial prefrontal cortex. Moreover, using a subsequent outcome devaluation manipulation, we show that this area is involved in guiding decision making when goal values change, even in the absence of external cues to guide performance. We can therefore exclude a purely Pavlovian account of ventromedial prefrontal function and unequivocally demonstrate its involvement in the acquisition as well as deployment of goal-directed knowledge.