V SMCs exhibit the remarkable plasticity required for development and adaptation of the cardiovascular system. The capacity of VSMCs to modulate their phenotype has evolved to facilitate angiogenesis and wound healing, but it has also been implicated in the pathogenesis of atherosclerosis, restenosis, posttransplant arteriopathy, and pulmonary hypertension. In this issue of the JCI, Boettger and colleagues report that the recently discovered Mir143/145 gene cluster promotes acquisition of the contractile phenotype of murine VSMCs (see the related article beginning on page 2634). These VSMC-restricted microRNAs, which target unique combinations of SMC genes, provide an efficient mechanism to fine-tune cardiovascular homeostasis and the response of the vessel wall to injury. This important discovery will open the door to new avenues of investigation and potentially future therapies for vascular diseases.