Leptin, a 167-amino acid peptide hormone produced by white adipose tissue, is primarily involved in the regulation of food intake and energy expenditure. Leptin receptors are expressed in many tissues including the cardiovascular system. Plasma leptin concentration is proportional to body adiposity and is markedly increased in obese individuals. Recent studies suggest that hyperleptinemia may play an important role in obesity-associated cardiovascular diseases including atherosclerosis. Leptin exerts many potentially atherogenic effects such as induction of endothelial dysfunction, stimulation of inflammatory reaction, oxidative stress, decrease in paraoxonase activity, platelet aggregation, migration, hypertrophy and proliferation of vascular smooth muscle cells. Leptin-deficient and leptin receptor-deficient mice are protected from arterial thrombosis and neointimal hyperplasia in response to arterial wall injury. Several clinical studies have demonstrated that high leptin level predicts acute cardiovascular events, restenosis after coronary angioplasty, and cerebral stroke independently of traditional risk factors. In addition, plasma leptin correlates with markers of subclinical atherosclerosis such as carotid artery intima-media thickness and coronary artery calcifications. Inhibition of leptin signaling may be a promising strategy to slow the progression of atherosclerosis in hyperleptinemic obese subjects.