Platelet-derived growth factor (PDGF) was identified in a search for serum factors that stimulate smooth muscle cell (SMC) proliferation. During the development of lesions of atherosclerosis that can ultimately lead to vessel occlusion, SMC are stimulated by inflammatory factors to migrate from their normal location in the media. They accumulate within the forming lesion where they contribute to lesion expansion by proliferation and deposition of extracellular matrix. Different genetic manipulations in vascular cells combined with various inhibitory strategies have provided strong evidence for PDGF playing a prominent role in the migration of SMC into the neointima following acute injury and in atherosclerosis. Other activities of PDGF identified in vivo suggest additional functions for PDGF in the pathogenesis of cardiovascular disease.