Putative endothelial progenitor cells play a role in organ regeneration, and their incompetence may be important in the development of chronic kidney disease. The mechanisms of this incompetence are broad and range from poor mobilization, viability, and engraftment to impaired differentiation into mature endothelial cells. By contrasting the role of endothelial progenitor cells in tissue regeneration with their developing incompetence in chronic kidney disease, we emphasize the importance of designing rational pharmacologic strategies to tackle such incompetence in the broader search for therapies to attenuate chronic disease.