Historically, revascularization of ischemic tissue was believed to occur through the migration and proliferation of endothelial cells in nearby tissues; however, evidence accumulated in recent years indicates that a subpopulation of adult, peripheral-blood cells, collectively referred to as endothelial progenitor cells (EPCs), can differentiate into mature endothelial cells. After ischemic insult, EPCs are believed to home to sites of neovascularization, where they contribute to vascular regeneration by forming a structural component of capillaries and by secreting angiogenic factors; new evidence indicates that EPCs can also differentiate into cardiomyocytes and smooth-muscle cells. These insights into the molecular and cellular processes of tissue formation suggest that cardiac function may be preserved after myocardial infarction by transplanting EPCs into ischemic heart tissue, thereby enhancing vascular and myocardial recovery. This therapeutic strategy has been effective in animal models of ischemic disorders, and results from randomized clinical trials suggest that cell-based strategies may be safe and feasible for treatment of myocardial infarction in humans and have provided early evidence of efficacy. However, the scarcity of EPCs in the peripheral blood and evidence that several disease states reduce EPC number and/or function have prompted the development of several strategies to overcome these limitations, such as the administration of genetically modified EPCs that overexpress angiogenic growth factors. To optimize therapeutic outcomes, researchers must continue to refine methods of EPC purification, expansion, and administration, and to develop techniques that overcome the intrinsic scarcity and phenotypic deficiencies of EPCs.