Chondroitin sulfate proteoglycans (CSPGs) of the arterial wall are generally considered to be atherogenic because of their ability to trap cholesterol-rich lipoproteins in vitro. Nevertheless, CSPGs are a diverse group of molecules with a long evolutionary history and distinct biologic functions. The three principal CSPGs in the arterial wall are versican, which is part of the hyalectan gene family; and decorin and biglycan, which are members of a separate gene family, the small leucine-rich proteoglycans. Importantly, there is now substantial evidence that the different molecular species of CSPGs participate unequally in lipoprotein retention, and that they exert unequal regulatory effects that are related to atherogenesis. Recently available murine models with genetic manipulations that affect CSPGs now allow causal studies of the roles of these molecules to be conducted in vivo, with occasionally surprising results. Moreover, tools are being developed to examine human genetic variations that are relevant to CSPGs, which may provide additional important insights into the human disease. The era in which proteoglycans are regarded as a nondescript backdrop, playing purely nonspecific structural roles, is over. Studies in manipulated animals and in human populations will continue to reveal precise, dynamic roles for these fascinating and ancient molecules.