Atherosclerosis and arterial injury–induced neointimal hyperplasia involve medial smooth muscle cell (SMC) proliferation and migration into the arterial intima. Because many 7-transmembrane and growth factor receptors promote atherosclerosis, we hypothesized that the multifunctional adaptor proteins -arrestin1 and -2 might regulate this pathological process. Deficiency of -arrestin2 in ldlr^-/- mice reduced aortic atherosclerosis by 40% and decreased the prevalence of atheroma SMCs by 35%, suggesting that -arrestin2 promotes atherosclerosis through effects on SMCs. To test this potential atherogenic mechanism more specifically, we performed carotid endothelial denudation in congenic wild-type, -arrestin1^-/-, and -arrestin2^-/- mice. Neointimal hyperplasia was enhanced in -arrestin1^-/- mice, and diminished in -arrestin2^-/- mice. Neointimal cells expressed SMC markers and did not derive from bone marrow progenitors, as demonstrated by bone marrow transplantation with green fluorescent protein (GFP) transgenic cells. Moreover, the reduction in neointimal hyperplasia seen in -arrestin2^-/- mice was not altered by transplantation with either wild-type or -arrestin2^-/- bone marrow cells. After carotid injury, medial SMC extracellular signal-regulated kinase activation and proliferation were increased in -arrestin1^-/- and decreased in -arrestin2^-/- mice. Concordantly, thymidine incorporation and extracellular signal-regulated kinase activation and migration evoked by 7-transmembrane receptors were greater than wild type in -arrestin1^-/- SMCs and less in -arrestin2^-/- SMCs. Proliferation was less than wild type in -arrestin2^-/- SMCs but not in -arrestin2^-/- endothelial cells. We conclude that -arrestin2 aggravates atherosclerosis through mechanisms involving SMC proliferation and migration and that these SMC activities are regulated reciprocally by -arrestin2 and -arrestin1. These findings identify inhibition of -arrestin2 as a novel therapeutic strategy for combating atherosclerosis and arterial restenosis after angioplasty.