Defects in the regulation of neo blood vessel growth (angiogenesis) or in vessel repair are major complications in many diseases, such as cancer, diabetes, atherosclerosis and myocardial infarction. In these diseases it was shown that the number of circulating endothelial progenitor cells (EPC) was altered. This has been associated with the angiogenic status and patient prognosis. However, the regulation of angiogenesis depends not only on the number of circulating EPC but also on their functions. EPC are bone marrow derived cells that are recruited into the peripheral blood in situations of vascular repair/angiogenesis or vascular stress. EPC are believed to exert their function using mainly two strategies: activating locally the endothelial cells and/or differentiating into mature endothelial cells that integrate the damaged vessels. To do this, EPC must home to “angiogenic active” sites, adhere to the activated/damaged endothelial cells or to the extracellular matrix and participate in the endothelial activation/repair process. In vitro and in vivo experiments using animal models revealed the importance of various signalling pathways in these processes and, in patients, new therapeutic strategies are being developed based on the specific functions of EPC. Although the role of EPC in vessel repair in disease is not totally understood, it becomes clear that the activation state of these cells is critical for the vessel repair process. Our previous work generated a detailed gene expression profile of EPC during the endothelial differentiation process in vitro. With this information, it has been possible to identify numerous molecular targets crucial for EPC differentiation and function and to test their involvement in EPC function during wound healing or tumor angiogenesis. The importance of EPC identification, activation state and function in vascular repair and in angiogenesis in disease will be discussed in this review.