Aging is associated with impairments in maintaining homeostasis in response to physiologic and environmental disturbances. These age-associated impairments include alterations in metabolic and neuroendocrine function. Leptin is a hormone mainly produced in and secreted by adipose tissue, and mutations in the leptin gene are associated with extreme obesity and neuroendocrine impairments, including impaired reproduction and low sex hormones, low thyroid hormone, low growth hormone, and elevated glucocorticoids. Leptin replacement reversed many of the phenotypes of leptin-deficient mice. Fasting reduces leptin gene expression and fasting-induced neuroendocrine alterations are also reversed by leptin injection. However, it was quickly apparent that leptin is highly correlated with total fat mass, and obesity is associated with elevated, rather than reduced, leptin levels in both rodents and humans. Thus, increased adiposity is associated with leptin resistance. Since aging is associated with dramatic changes in adiposity and neuroendocrine impairments similar to those observed in leptin-deficient and leptin-resistant animals, leptin resistance and/or insufficiency might contribute to some of these age-related metabolic impairments.