Very small embryonic-like stem cells (VSELs) represent a population of extremely small nonhematopoietic pluripotent cells that are negative for lineage markers and express Sca-1 in mice and CD133 in humans. Their embryonic-like characteristics include the expression of markers of pluripotency; the ability to give rise to cellular derivatives of all three germ-layers; and the ability to form embryoid-like bodies. Indeed, quiescent VSELs may represent the remnants of epiblast-derived cells in adult organs. After tissue injury, including acute myocardial infarction (MI), bone marrow-derived VSELs are mobilized into the peripheral blood and home to the damaged organ. Given the ability of VSELs to differentiate into cardiomyocytes and endothelial cells, and their ability to secrete various cardioprotective growth factors/cytokines, VSELs may serve as an ideal cellular source for cardiac repair. Consistently, transplantation of VSELs after an acute MI improves left ventricular (LV) structure and function, and these benefits remain stable during long-term follow-up. Although the mechanisms remain under investigation, effects of secreted factors, regeneration of cellular constituents, and stimulation of endogenous stem/progenitors may play combinatorial roles. The purpose of this review is to summarize the current evidence regarding the biologic features of VSELs, and to discuss their potential as cellular substrates for therapeutic cardiac repair.