Leptin, a 167 amino-acid product of the ob or LEP gene, was first reported in 1994 after a 40-year search that began following the emergence of a mutant strain of mice with hyperphagia, early on-set obesity, and delayed sexual maturation. Since then, leptin deficiency has also been reported in the rat, and more recently in humans. It is secreted constitutively primarily by the white adipose tissue, and in smaller quantities by a number of non-adipose tissues. It acts by binding to specific membrane bound leptin receptors, belonging to the class 1 cytokine receptor family, and activating the JAK-STAT system. Leptin regulates appetite and body weight mainly through its actions on the hypothalamus involving the NPYmelanocortin pathway, and, to a lesser extent, through increased energy expenditure by way of sympathoactivation and increased substrate cycling. Its effects on reproduction, puberty in particular, are mediated through actions on the hypothalamic-pituitary-gonadal axis and on the gonads. Leptin also appears to have permissive roles in CNS development during the neonatal period, bone growth and development, and in haemopoietic and immune functions. Although it was its deficiency state that first led to its discovery, it now appears that the clinical significance of leptin lies not only in the consequences of its deficiency but also when it is in excess as occurs in obesity. Emerging evidence is implicating leptin as a link between obesity associated cardiovascular disease risks and infertility. Besides this, leptin is also being implicated as a growth factor in cancer. The story that started with a search for a body weight regulating factor is now unfolding into one that is revealing roles for leptin that stretch beyond the regulation of appetite and body weight.