The burgeoning obesity epidemic has fueled the drive to describe, mechanistically, metabolic homeostasis. From the early theories implicating glucose as a principal modulator grew an understanding of a complex array of metabolic signals, sensed by peripheral organs along with specific locations within the central nervous system (CNS). The discovery that leptin, an adipose-derived hormone, acts within the mediobasal hypothalamus to control food intake and energy expenditure ushered in a decade of research that went on to describe not only the specific nuclei and cell type, such as proopiomelanocortin neurons of the arcuate nucleus, that respond to leptin but also the signaling cascades that mediated its effects. This review thus highlights the sites and mechanisms of action of leptin, both in the hypothalamus and in extrahypothalamic sites within the CNS, and shows our current knowledge and direction of future research aimed at understanding the multifunctional role of leptin in maintaining metabolic homeostasis.