Vascular smooth muscle cells (SMC) can modulate their genetic program of differentiation in a variety of disease contexts such as atherosclerosis, hypertension, asthma, intestinal or bladder obstruction, cancer, and Alzheimer's disease. A critical regulator for the establishment and maintenance of the SMC differentiation program is the SRF-Myocardin transcriptional switch which is sufficient to turn on SMC cytoskeletal and contractile genes and enable SMC-like contraction in non-SMC types. Myocardin levels and activity are perturbed in several human diseases as well as animal models of disease. Thus, a major question is how Myocardin levels are maintained. We recently have shown that TGF-beta 1, a known inducer of SMC differentiation, up-regulates expression of Myocardin. Moreover, a screen for TGF-beta 1- inducible microRNAs has revealed dramatic up- regulation of the miR-143/145 bicistronic gene. Interestingly, miR-145 appears to up-regulate Myocardin through an ill-defined mechanism. In addition to miR-143/145, we report the modulated expression of several additional miRs whose functions are unknown. Expression and activity of TGF-beta 1 modulated miRs will be presented with emphasis on their role in the establishment of a SMC differentiated phenotype.