Depersonalization remains a fascinating and obscure clinical phenomenon. In addition to earlier Jacksonian neurobiological adumbrations, and conventional psychodynamic accounts, views started to be expressed in the 1930s that depersonalization might be a vestigial form of behavior, and since the 1960s that it might be a phenomenon related to the temporal lobe. Recent advances in the neurobiology of the limbic system, and the application of Geschwind's concept of disconnection in the corticolimbic system, have opened the possibility of developing testable models. This paper includes a review of these ideas and of the clinical features of depersonalization, particularly of its emotional changes, suggesting that they are important for the neurobiological understanding of depersonalization. It also draws attention to clinical similarities between the experiential narratives produced by patients suffering from depersonalization and those with corticolimbic disconnections. On the basis of this, a new model is proposed according to which the state of increased alertness observed in depersonalization results from an activation of prefrontal attentional systems (right dorsolateral prefrontal cortex) and reciprocal inhibition of the anterior cingulate, leading to experiences of "mind emptiness" and "indifference to pain" often seen in depersonalization. On the other hand, a left-sided prefrontal mechanism would inhibit the amygdala resulting in dampened autonomic output, hypoemotionality, and lack of emotional coloring that would in turn, be reported as feelings of "unreality or detachment."