Apoptosis, the regulated destruction of a cell, is characterized by biological and morphological changes and involves a large web of integrating pathways and factors. Apoptosis is necessary to eliminate excess cells and cells that hinder development, and hence the importance of apoptotic pathways and apoptotic agents in removing adipocytes for the treatment of obesity has been recently explored. Leptin was widely recognized for its ability to regulate adipose tissue mass by influencing food intake and energy expenditure. Recent findings, however, demonstrated that leptin treatment initiated apoptosis in adipose tissue. Leptin-induced adipocyte apoptosis was a surprising finding, as adipocytes were thought to be extremely stable; however, both pro- and anti-anti-apoptotic effects of leptin have been demonstrated in several cell types. In particular, anti-apoptotic effects have been shown in certain types of cancer cells, and are correlated with the presence of leptin receptors. While leptin’s effects on energy balance, including induction of adipocyte apoptosis, are primarily mediated by the central nervous system, it is possible that anti-apoptotic effects of leptin are mediated through autocrine or paracrine effects. In this chapter both anti-apoptotic and pro-apoptotic effects of leptin in several cell types are reviewed.