Given the well-defined role of LIM-motif containing proteins in cytoskeletal organization, cell fate, and differentiation, we hypothesized that the regulation of LIM proteins played an integral role in vascular remodeling. We screened a compendium of cDNA microarray data from rat vascular smooth muscle cells (VSMC) for novel LIM-containing targets and identified muscle LIM protein (MLP), a gene previously thought to be only in striated muscle. Sequence analysis, RTQPCR and Western blotting reconfirmed expression of MLP in VSMC. MLP was elevated > 10-fold 7 days following balloon injury in the rat carotid artery. Wire injury led to a significantly increased intima/media ratio in MLP -/- mice compared to wild-type controls (P < 0.007, N = 5). Fas-ligand and ceramide-induced apoptosis were significantly decreased in MLP deficient VSMC (n = 6, P < 0.001). Adenoviral-induced restoration of MLP significantly restored apoptotic response (N = 6, P < 0.001). These findings are the first to identify MLP in vascular smooth muscle and demonstrate that it plays a critical role in vascular remodeling. This is consistent with earlier findings demonstrating a role for MLP in striated muscle remodeling in response to load and stretch.