Differentiated smooth muscle cells (SMCs) remain highly plastic, enabling them to alter their phenotype in response to environmental and pathologic stimuli. SMCs in vascular pathologies such as atherosclerosis exhibit phenotypes clearly different from those of the mature cells in normal blood vessels. These phenotypically modulated SMCs play an integral role in the development of vascular diseases. This review addresses recent progress in our understanding of the mechanisms that control SMC phenotype during vascular development and in vascular disease. A particular focus is on the transcriptional control programs of the differentiated state of SMCs.