In this review we discuss the role of pigment epithelium-derived factor (PEDF) as a possible new target molecule to therapeutically influence cardiovascular disease. PEDF is a multifunctional, pleiotropic protein with antiangiogenic, antitumorigenic, antioxidant, anti-inflammatory, antithrombotic, neurotrophic and neuroprotective properties. First identified in retinal pigment epithelium cells, it is expressed in various tissues throughout the body such as the eye, liver and adipose tissue. Recently PEDF has also been characterized in the heart. PEDF has been suggested to have a protective role in atherosclerosis, the main cause of coronary heart disease, myocardial infarction and heart failure due to its anti-inflammatory, antioxidant and antithrombotic effects in the vessel wall and platelets. Additionally PEDF has strong antiangiogenic effects by inducing apoptosis in endothelial cells and by regulating the expression of other angiogenic factors. Therefore blocking of PEDF locally for example in ischemic tissue in the heart might favour angiogenesis, induce neovascularization and lead to increased perfusion of the injured tissue. On the other hand, local overexpression of PEDF restricted to atherosclerotic lesions might block angiogenesis, inflammation and thrombosis at these sites and thus counteract destabilization and rupture of the lesion otherwise caused by inflammatory activation and excessive angiogenesis and inhibit subsequent thrombus formation.