Serum response factor (SRF) is a widely expressed transcription factor involved in orchestrating disparate programs of gene expression linked to muscle differentiation and cellular growth. Vascular smooth muscle cell (SMC) differentiation, for example, is marked by the coordinate expression of several contractile and cytoskeletal genes regulated directly by SRF through one or more CArG-box elements in the immediate vicinity of transcription start sites. In vascular disease, this CArG-dependent program of SMC differentiation is compromised and numerous CArG-dependent early growth-response genes are activated. Thus, SRF must toggle between programs of SMC differentiation and growth depending on local environmental cues. Moreover, SRF must distinguish between a course of SMC differentiation and programs of cardiac and skeletal muscle differentiation. Several mechanisms exist to ensure context- and cell-specific programs of SRF-dependent gene expression. These include regulated expression, DNA binding, and alternative splicing of SRF, flanking sequences adjacent to and chromatin remodeling of CArG boxes, RhoA-mediated alterations in the cytoskeleton, and association of SRF with a variety of cell-restricted cofactors including the recently discovered myocardin coactivator. Although many SMC-differentiation genes require critical evolutionarily conserved CArG boxes for SMC-restricted promoter activity in cultured cells and transgenic mice, the expression of a growing number of similarly restricted genes appears to be independent of SRF. Thus, parallel circuits of gene transcription have evolved for the appropriate expression of all genes that define mammalian SMC lineages. The purpose of this review is to summarize the history and progress made in SRF research with emphasis on the role this transcription factor plays in facilitating a program of SMC-restricted gene expression.