Tight control of smooth muscle cell (SM) proliferation, differentiation, and apoptosis requires a balance between signaling and transcriptional events. Recent developments in vascular research revealed that serum response factor (SRF) function is important for the regulation of each of these processes. The cloning and characterization of several SM specific genes and the discovery that SRF is central for their expression fueled studies aimed at understanding the role of molecular partners including co-activators and co-repressors. Perturbations of pathways involving SRF are associated with abnormalities in the myogenic program and aberrant phenotypic consequences. Surprisingly, studies on airway SM have remained an underrepresented area of investigation. Our laboratory described a novel regulatory mechanism of SRF function in airway myocytes by modulation of its subcellular localization. This review summarizes current knowledge on the structure and function of this essential transcription factor as well different modes of regulating SRF expression and activity that are becoming key players in directing SM function in health and disease.