During the development of atherosclerotic lesions in humans or after hypercholesterolemia or deendothelialization in experimental animals, vascular smooth muscle cells (SMCs) proliferate and migrate from the media into the intima. SMCs implicated in this process show a remodeling of morphological and cytoskeletal features, which consists of a loss of microfilament bundles and a switch of actin isoform expression from α-smooth muscle to β-cytoplasmic predominance. Similar features are observed in SMCs of fetal animals, and when SMCs are placed in culture. SMCs show changes of proliferative activity and differentiation upon the stimulation with factors released from platelets, endothelial cells, T lymphocytes and macrophages, such as platelet-derived growth factor, fibroblast growth factor or γ-interferon. Extracellular matrix components such as heparin can also modulate SMC phenotypic changes. Studies on cell-cell interaction mechanisms mediated by these substances could help in the understanding of atherosclerotic plaque formation and in the planification of strategies for the prevention of this disease.