Since their initial discovery, endothelial progenitor cells (EPCs) have held tremendous promise for cell therapy for a variety of cardiovascular diseases including pulmonary hypertension. The clinical experience to date suggests that circulating or bone marrow mononuclear cells and EPCs can induce neovascularization, and enhance cardiac repair after myocardial function, as well as improvements in the hemodynamic and functional status of patients with idiopathic pulmonary arterial hypertension. Although these results are promising, the overall magnitude of the clinical benefits seen in these trials appear to be rather modest. Indeed, strong experimental evidence points towards a reduction in mobilization and impairment in function of EPCs in preclinical models and patients with cardiac disease or with cardiovascular risk factors such as advanced age, type I and II diabetes, hypercholesterolemia, coronary artery disease, as well as other conditions such as pulmonary hypertension. Genetic engineering of EPCs ex vivo, prior to transplantation, is a promising cell-enhancement strategy for restoring the angiogenic potential of autologous, patient-derived cells. This review provides an update of the experimental studies that have used gene-modified EPC therapy to treat ischemic cardiovascular disease and pulmonary hypertension.