Vascular smooth muscle cells exhibit varied responses after vessel injury and surgical interventions, including phenotypic switching, migration, proliferation, protein synthesis, and apoptosis. Although the source of the smooth muscle cells that accumulate in the vascular wall is controversial, possibly reflecting migration from the adventitia, from the circulating blood, or in situ differentiation, the intracellular signal transduction pathways that control these processes are being defined. Some of these pathways include the Ras-mitogen-activated protein kinase, phosphatidylinositol 3-kinase-Akt, Rho, death receptor-caspase, and nitric oxide pathways. Signal transduction pathways provide amplification, redundancy, and control points within the cell and culminate in biologic responses. We review some of the signaling pathways activated within smooth muscle cells that contribute to smooth muscle cell heterogeneity and development of pathology such as restenosis and neointimal hyperplasia.