The cell surfaces and surrounding extracellular matrix of the cardiovascular system possess large quantities of heparan sulfate proteoglycans (HSPGs) 1 (1). These highly charged macromolecules consist of different core proteins with covalently linked heparan sulfate chains (HS) of varying monosaccharide sequence which serve as critical mediators of biologic processes (2, 3). For example, these components are involved in regulating mesodermal cell fate, positioning of the heart, vasculogenesis and angiogenesis after ischemic injury, interactions of cells with adhesive proteins and blood vessels, proliferation of smooth muscle cells during atherogenesis, metabolism of lipoproteins, nonthrombogenic characteristics of endothelial cells, etc.(4–9). Detailed investigations over the past decade have defined the structures of HSPGs, uncovered the molecular mechanisms by which these components carry out their diverse functions, and revealed that specific monosaccharide sequences of HS are required for interaction with biologic targets. In this review, we outline the current state of our knowledge about the structure and the biosynthesis of HSPGs as well as describe interactions of these components with growth factors, enzymes, and protease inhibitors. These observations provide a conceptual framework for elucidating the roles of HSPGs in other biologic systems.