Three different families of proteoglycans, which include chondroitin sulfate (CSPG), dermatan sulfate (DSPG) and heparan sulfate (HSPG), and hyaluronan accumulate in the extracellular matrix of vascular lesions and influence vascular cell phenotype. Hyaluronan forms pericellular coats around arterial smooth muscle cells (ASMCs) and this molecule increases both inside and outside of cells stimulated to divide. Interference of hyaluronan binding to hyaluronan receptors on the surface of ASMCs blocks PDGF induced proliferation and migration. Versican is the major interstitial CSPG that accumulates in restenotic lesions. Versican is synthesized as multiple mRNA spliced variants (V0, V1, V3) by ASMCs. Overexpression of versican by cell mediated gene transfer alters ASMC phenotype and influences ECM composition in blood vessels subjected to experimental injury. Decorin is a small DSPG that inhibits TGF-β1 activity when overexpressed by ASMC transduced with decorin cDNA. Transfer of decorin overproducing cells into injured arteries reduces intimal thickening and stimulates collagen deposition. Decorin is also synthesized by vascular endothelial cells during sprouting and tube formation in vitro. The ability of decorin to stabilize the ECM may be critical to the neovascularization of vascular lesions. Heparan sulfate proteoglycans partially regulate ASMC migration. Removal of HSPGs from injured arteries by heparinase treatment is effective in reducing the mitogenic response induced by bFGF in arterial smooth muscle cells. Collectively, these studies indicate that not only do proteoglycans contribute to the mass of restenotic lesions but they also have a dramatic effect on altering ASMC phenotype.