Cardiovascular disease is the leading cause of death worldwide. Despite significant progress in understanding of the disease mechanisms, most therapies remain at best palliative. Few therapeutic approaches offer direct tissue repair and regeneration. Cell-based therapy offers a promising approach that involves transplantation of healthy and functional cells to replenish damaged cells and repair injured tissue. Endothelial dysfunction is one of the most important mechanisms of cardiovascular disease, thus endothelial progenitor cells (EPC) and their derivatives have been investigated as a potential source for cell therapy. In pre-clinical and pilot clinical studies, treatment with EPCs or their derivatives as well as their co-transplantation with other cell types has shown some initial promising results. In this review, we will first describe the importance of endothelial cells and EPC homeostasis in the pathophysiology of cardiovascular disease. The potential sources of EPCs, including their isolation and purification, differentiation from pluripotent stem cells and adult stem cells, and trans-differentiation from somatic cells will then be summarized. Lastly, the application of target genome editing tools, such as Zinc Finger Nuclease (ZFN), Transcription Activator Like Effector Nucleases (TALEN) and RNA Guided Endo Nuclease (RGEN) to modify EPCs and their derivatives will be described. These technologies promise to further improve the therapeutic potential of EPCs and their derivatives to treat cardiovascular disease.