The dopaminergic midbrain, which comprises the substantia nigra and ventral tegmental area (SN/VTA), plays a central role in reward processing. This region is also activated by novel stimuli, raising the possibility that novelty and reward have shared functional properties. It is currently unclear whether functional aspects of reward processing in the SN/VTA, namely, activation by unexpected rewards and cues that predict reward, also characterize novelty processing. To address this question, we conducted an fMRI experiment during which subjects viewed symbolic cues that predicted either novel or familiar images of scenes with 75% validity. We show that SN/VTA was activated by cues predicting novel images as well as by unexpected novel images that followed familiarity-predictive cues, an ‘unexpected novelty’ response. The hippocampus, a region implicated in detecting and encoding novel stimuli, showed an anticipatory novelty response but differed from the response profile of SN/VTA in responding at outcome to expected and ‘unexpected’ novelty. In a behavioral extension of the experiment, recollection increased relative to familiarity when comparing delayed recognition memory for anticipated novel stimuli with unexpected novel stimuli. These data reveal commonalities in SN/VTA responses to anticipating reward and anticipating novel stimuli. We suggest that this anticipatory response codes a motivational exploratory novelty signal that, together with anticipatory activation of the hippocampus, leads to enhanced encoding of novel events. In more general terms, the data suggest that dopaminergic processing of novelty might be important in driving exploration of new environments.