Leptin has received much attention since its cloning in 1994. Initially, leptin research centered on satiety, energy balance and sympathetic activation. However, hyperleptinemia has since been identified as an independent risk factor for various cardiovascular pathologies including atherosclerotic coronary artery disease. Over the last decade, multiple studies have implicated leptin as an important mediator in endothelial dysfunction and neointimal hyperplasia, both key steps in the evolution of atherosclerotic vascular changes. Additionally, more recent evidence indicates that paracrine leptin release from perivascular adipose tissue (PVAT) has deleterious effects on the underlying endothelium and vascular smooth muscle cells (SMC), including the coronary circulation. This report reviews pertinent literature on leptin-mediated endothelial dysfunction, SMC proliferation and the role of PVAT-derived leptin with an emphasis on the coronary circulation and discussions of currently proposed molecular mechanisms of PVAT-mediated coronary endothelial dysfunction and neointimal hyperplasia.