Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and immune homeostasis. Leptin links nutritional status and proinflammatory T helper 1 immune responses, and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. This review focuses on the multiple roles of leptin in chronic inflammation and autoimmunity and suggests new possible therapeutic implications for leptin modulators.