Arterial wall injury either by balloon catheter, drying, or scraping results in a denudation of endothelial cells (EC) and a subsequent proliferation of smooth-muscle cells (SMC). The degree of SMC proliferation appears to be dependent on the degree of initial injury and not to the loss of the overlying endothelium. Successful reendothelialization of denuded areas depends on the size of the denuded segment as well as SMC-EC interactions. Prolonged exposure of SMC to serum substances results in inhibition of EC regrowth, the production of prostacyclin by SMC, and the development of a thromboresistant surface. Heparin appears to inhibit SMC proliferation in vivo (as well as in vitro), an effect that is independent of platelet SMC interaction. EC-derived heparin in vivo may also result in inhibition of SMC proliferation. Platelets may play an important role in the early response to arterial injury and development of myointimal hyperplasia (MIH), but their long-term role appears to be minor. Antiplatelet agents have widely varying species-dependent effects on platelets and platelet-vessel wall interactions, but in specific circumstances they may inhibit MIH. The precise role of steroid drugs and immunosuppression on MIH in arterial injury models awaits further study. The role of lipoproteins in MIH is unclear; however, the inhibition of MIH by omega-3 fatty acids in vivo as well as their inhibition of platelet-derived growth factor production by EC in vitro implies a regulatory role. Acute hypertension results in a marked proliferation of EC and SMC in vivo and enhances the proliferative response to injury as well. Low wall shear stress, turbulence, and boundary layer separation all increase EC turnover, a likely influence on EC growth factor production. The compliance mismatch resulting from graft-artery anastomoses, injury, and endarterectomy results in locally increased cyclical stretch, which may predispose to SMC proliferation.