Despite long-standing knowledge about the relationship between thrombosis and atherosclerosis, the specific role of thrombin in modulating atherosclerosis and the response to vascular injury is not well understood. Thrombin receptor stimulation in vitro signals many cellular events that are associated with the response to vascular injury (atherosclerosis) in vivo. Proliferation of smooth muscle cells (SMCs) is an important component of the response to vascular injury. We have previously shown that human alpha-thrombin and the 14-amino acid human thrombin receptor-activating peptide (huTRAP-14) stimulate proliferation of cultured rat aortic SMCs. However, thrombin-induced SMC proliferation demonstrates delayed kinetics relative to platelet-derived growth factor (PDGF-BB, another potent SMC mitogen). Several mechanisms may be responsible for these delayed kinetics in vitro, including production of necessary secondary growth factors and thrombin-induced upregulation of its receptor. In vivo studies have demonstrated that thrombin inhibition limits the response to vascular injury in a hypercholesterolemic rabbit model of focal femoral atherosclerosis. However, this effect does not appear to be mediated by effects on early SMC proliferation. In this discussion, we will address the mechanisms of thrombin-induced SMC proliferation in vitro and apply this knowledge to our understanding of the role of thrombin inhibition in limiting the response to vascular injury in vivo.