Endothelial progenitor cells (EPCs) participate in vascular healing during both acute injury and chronic disease. The quantity and quality of circulating EPCs correlate inversely with the severity of vascular disease, such that reduced number and/or function of EPCs are significant independent risk factors for impaired healing capacity, dysfunctional endothelium, and progression of atherosclerosis and vascular disease. EPC therapy assists healing of cardiac and limb ischemia and has great potential for improving the quality of life and longevity of patients with severe cardiovascular and peripheral vascular disease who are not candidates for conventional revascularization procedures. In addition, EPCs can be used to promote vascular graft patency. This review focuses on the characterization of EPCs, positive and negative regulators of EPCs, the role of EPCs in vascular disease, and the potential for EPC therapy to ameliorate the sequelae of severe peripheral vascular disease.