Endothelial progenitor cells (EPCs) are a subset of the total mononuclear cell population (tMNCs) that possess an enhanced potential for differentiation within the endothelial-cell lineage. Typically, EPCs are selected from tMNCs via the expression of both hematopoietic stem-cell markers and endothelial-cell markers, such as CD34, or by culturing tMNCs in media selective for endothelial cells. Both EPCs and tMNCs participate in vascular growth and regeneration, and their potential use for treatment of myocardial injury or disease has been evaluated in early-phase clinical studies. Direct comparisons between EPCs and tMNCs are rare, but the available evidence appears to favor EPCs, particularly CD34+ cells, and the potency of EPCs may be increased as much as 30-fold through genetic modification. However, these observations must be interpreted with caution because clinical investigations of EPC therapy are ongoing. We anticipate that with continued development, EPC therapy will become a safe and effective treatment option for patients with acute myocardial infarction or chronic ischemic disease. J. Cell. Physiol. 219: 235–242, 2009. © 2008 Wiley-Liss, Inc.