Therapeutic angiogenesis/vasculogenesis represents a new approach to treat patients with ischemic disease not curable with conventional treatment. This review focuses on the rationale and preliminary results of combining stem cell and gene therapy for regenerative medicine. Under disease conditions, impaired neovascularization results from diminished vascular growth factor production and primary dysfunction of endothelial cells and their progenitors. Advances in our ability to genetically manipulate cells ex vivo has provided the technological platform to implement stem cell biology and circumvent the potential hazard of direct gene transfer. Ex vivo engineered endothelial progenitor cells have been used for the treatment of peripheral limb ischemia. The approach eliminates the drawback of immune response against viral vectors and makes feasible repeating the therapeutic procedure in case of injury recurrence. The strategy of using stem cells as vectors for curative agents proved to be of value for the treatment of pulmonary hypertension and thrombosis. Transplantation of neural stem cells genetically modified to secrete nerve growth factor was able to ameliorate the death of striatal projection neurons caused by transient focal ischemia in the adult rat. By a similar approach, engineered neural stem cells might be used for treating neurodegenerative disorders. Therefore, genetic manipulation of stem cells opens new avenues for regenerative medicine.