Cholesterol is an essential structural component of cellular membranes. In addition to the structural role, it also serves as a precursor to a variety of steroid hormones and has diverse functions in intracellular signal transduction. As one of its functions in cell signaling, recent evidence suggests that cholesterol plays a key role in regulating angiogenesis. This review discusses the role of cholesterol in angiogenesis, with a particular emphasis on cholesterol traffcking in endothelial cell signaling. Small molecule inhibitors of cholesterol traffcking and their preclinical and clinical development targeting angiogenesis and cancer are also discussed.