We summarize the biological impact of leptin signaling as well as the molecular and cellular characteristics of leptin action. Our focus is principally in the central nervous system and we describe the properties of the neuronal networks that are mediators of leptin's effects on ingestive behavior, energy balance, and the reproductive system. The molecular targets of leptin's effects are also responsible for the attenuation and termination of the intracellular signal transduction pathway for leptin, providing a clear understanding of the mechanisms leading to leptin resistance or insensitivity. Using the tools of comparative biology, we explore the potential functions of leptin in fish and birds. Based on the highly variable expression of leptin in multiple tissues, a clear lack of expression of leptin in adipocytes in numerous species of fish and birds and an absence of changes of leptin concentrations in blood that are correlated with changes in nutritional status, it is clear that leptin is unlikely to function as a signal for triglyceride stores in nonmammalian species. This comparative survey serves to highlight the unique function of leptin in mammalian biology as a modulator of energy balance, sexual development, and fertility. © 2018 American Physiological Society. Compr Physiol 8:351‐369, 2018.