The orbitofrontal cortex is strongly connected with limbic areas of the medial temporal lobe that are critically involved in the establishment of declarative memories (entorhinal and perirhinal cortex and the hippocampal region) as well as the amygdala and the hypothalamus that are involved in emotional and motivational states. The present article reviews evidence regarding the role of the orbitofrontal cortex in the processing of novel information, breaches of expectation, and memory. Functional neuroimaging evidence is provided that there is a difference between the anterior and posterior orbitofrontal cortex in such processing. Exposure to novel information gives rise to a selective increase of activity in the granular anterior part of the orbitofrontal cortex (area 11) and this activity increases when subjects attempt to encode this information in memory. If the stimuli violate expectations (e.g., inspection of graffiti-like stimuli in the context of other regular stimuli) or are unpleasant (i.e., exposure to the sounds of car crashes), there is increased response in the posteromedial agranular/dysgranular area 13 of the orbitofrontal region. The anatomic data provide a framework within which to understand these functional neuroimaging findings.