An imbalance between calorie intake and energy expenditure produces obesity. It has been a major problem in societies of the developing and developed world. In obesity an excessive amount of fat accumulates in adipose tissue cells as well as in other vital organs like liver, muscles, and pancreas. The adipocytes contain ob genes and express leptin, a 16 kDa protein. In the present communication, we reviewed the molecular basis of the etiopathophysiology of leptin in obesity. Special emphasis has been given to the use of leptin as a drug target for obesity treatment, the role of diet in the modulation of leptin secretion, and reduction of obesity at diminished level of blood leptin induced by physical exercise.