Great strides have been made in understanding the genetics of body weight regulation, in part due to the study of rodent models of obesity that are characterized by mutations affecting leptin or its receptors. Leptin, produced in adipose tissue, acts both centrally and peripherally to orchestrate complex metabolic and behavioral changes that increase loss of adipose tissue, including suppressing food intake and increasing thermogenesis. In addition, recent evidence indicates that leptin acts centrally to trigger an apoptotic process resulting in adipocyte deletion. Loss of adipocytes by apoptosis may provide an explanation for the unexpected delay in return to initial energy status following leptin treatments. This review summarizes the major aspects of leptin-induced adipose tissue apoptosis, including some of the newest findings about possible mechanisms of action.