Leptin has been shown to have a wide repertoire of peripheral effects, some of which are mediated through the central nervous system and others that are induced through a direct action on target tissues. There is now evidence showing that leptin exerts some of its metabolic effects acting directly on peripheral tissues. The role of leptin has expanded from a narrow position in obesity to effects on biological processes, such as diabetes, appetite, thermogenesis, the immune system and reproduction. Here in a first part, we review preclinical evidence for direct effects on specific tissues (neurons, liver and muscle) and metabolic pathways. In a second part we review clinical evidence for leptin effects. In particular we review the effects of recombinant human leptin in lean, obese, diabetic subjects and in patients with congenital leptin deficiency or lipoatrophic diabetes. Additionally, while clinic leptin has not shown dramatic effects in obese / diabetic subjects with measurable serum leptin, in states of leptin deficiency treatment with leptin has been shown to have profound effects on body weight and appetite and insulin resistance.