EARLY studies of brain glucose metabolism established the axiom that insulin is not required for utilization of glucose by the central nervous system (CNS) (1). A corollary to this concept was the belief that circulating insulin is incapable of crossing the bloodbrain barrier (BBB) and is therefore without effects in the brain. While the first of these tenets remains unchallenged, the second has been subjected to detailed scrutiny for over a decade, following the identification of both insulin (2) and its receptor (3) in the adult mammalian brain. Early reports of relatively high concentrations of insulin in brain extracts raised the possibility that insulin is synthesized and released locally in the CNS, as had been established for several other peptide hormones (2). Recent investigations, however, indicate that “brain insulin” is derived largely from the circulation (4), and a growing body of evidence suggests that its delivery into the neuropil may be facilitated by a specialized BBB transport system (5, 6). Moreover, insulin produces marked effects on food intake behavior and is implicated in the central regulation of autonomic function. Thus, although our current understanding of the roles played by insulin in the brain is far from complete, the early perception of the brain as an insulin-insensitive tissue can no longer be considered tenable. In this article, we review recent literature related to the hypothesis that insulin is an afferent CNS signal which regulates normal energy balance.