In 1968, Professor Robert Wissler published a landmark review on the role of smooth muscle cells in atherogenesis. He suggested that in future studies more attention should be given to the cytologic and metabolic characteristics of these multifunctional mesenchymal cells. This article summarizes some of our studies inspired by these words and indicates a few of the many questions that still need to be addressed. We have shown that smooth muscle cells of different phenotypes from that expressed in normal arterial media exist in regions of diffuse intimal thickenings adjacent to atheroma and also in vessels following injury. Cells of equivalent phenotype can exist in cell culture, and we have shown that they have all the characteristics of smooth muscle in atherogenesis, ie, they proliferate in response to mitogens, readily synthesize increased amounts of extracellular matrix, and accumulate large amounts of lipid. In contrast, smooth muscle cells of the phenotype that normally exists in the unaffected artery do not express these characteristics and their major function is maintenance of vessel tone. Thus a deeper knowledge of the factors that control smooth muscle phenotype is essential to an understanding of the mechanisms underlying the pathogenesis of atherosclerosis.