Leptin is well known as a hormone important in the central control of appetitive behaviors via receptor-mediated actions in the hypothalamus, where leptin adjusts food intake to maintain homeostasis with the body’s energy stores. Recent evidence has shown that leptin and its receptors are widespread in the CNS and may provide neuronal survival signals. This review summarizes our current knowledge of how leptin functions in the brain and then focuses on the ability of leptin to mitigate neuronal damage in experimental models of human neurological disorders. Damage to the brain by acute events such as stroke, or long-term loss of neurons associated with neurodegenerative diseases, including Parkinson’s and Alzheimer’s disease, may be amenable to treatment using leptin to limit death of susceptible cells. Leptin-mediated pro-survival signaling is now known to prevent the death of neurons in these models. The signaling cascades that leptin generates are shared by other neuroprotective molecules including insulin and erythropoietin, and are thus a component of the neurotrophic effects mediated by endogenous hormones. Coupled with evidence that leptin dysregulation in human disease also results in enhanced neuronal susceptibility to damage, development of leptin as a therapeutic methodology is an attractive and viable possibility.