Circulating endothelial progenitor cells (EPCs) are believed to home to sites of neovascularization, contributing to vascular regeneration either directly via incorporation into newly forming vascular structures or indirectly via the secretion of pro-angiogenic growth factors, thereby enhancing the overall vascular and hemodynamic recovery of ischemic tissues. The therapeutic application of EPCs has been shown to be effective in animal models of ischemia, and we as well as other groups involved in clinical trials have demonstrated that the use of EPCs was safe and feasible for the treatment of critical limb ischemia and cardiovascular diseases. However, many issues in the field of EPC biology, especially in regard to the proper and unambiguous molecular characterization of these cells, still remain unresolved, hampering not only basic research but also the effective therapeutic use and widespread application of these cells. Further, recent evidence suggests that several diseases and pathological conditions are correlated with a reduction in the number and biological activity of EPCs, making the development of novel strategies to overcome the current limitations and shortcomings of this promising but still limited therapeutic tool by refinement and improvement of EPC purification, expansion, and administration techniques, a rather pressing issue.