Abstract-Most common cardiovascular diseases are accompanied by endothelial dysfunction. Because of its predominant role in the pathogenesis of cardiovascular disease, the vascular endothelium is an attractive therapeutic target. The identification of promoter sequences capable of rendering endothelial-specific transgene expression together with the recent development of vectors with enhanced tropism for endothelium may offer opportunities for the design of new strategies for modulation of endothelial function. Such strategies may be useful in the treatment of chronic diseases such as hypertension, atherosclerosis, and ischemic artery disease, as well as in acute myocardial infarction and during open heart surgery for prevention of ischemia and reperfusion (I/R)-induced injury. The recent identification of putative endothelial progenitor cells in peripheral blood may allow the design of autologous cell-based strategies for neovascularization of ischemic tissues and for the repair of injured blood vessels and bioengineering of vascular prosthesis. "Proof-of-concept" for some of these strategies has been established in animal models of cardiovascular disease. However the successful translation of these novel strategies into clinical application will require further developments in vector and delivery technologies. Further characterization of the processes involved in mobilization, migration, homing, and incorporation of endothelial progenitor cells into the target tissues is necessary, and the optimal conditions for therapeutic application of these cells need to be defined and standardized. T he vascular endothelium (VE) plays a pivotal role in the regulation of vascular function and homeostasis. 1 In normal conditions, the VE elaborates a variety of substances that influence vascular tone and protect the vessel wall against inflammatory cell adhesion, thrombus formation, and vascular cell proliferation. [2][3][4] Pathological conditions caused by increased oxidative stress, hyperlipidemia, and inflammation lead to endothelial dysfunction, which is characterized by reduced availability of vasodilatory and anti-adhesion substances, such as nitric oxide (NO) and prostacyclin, and concomitant increases in vasoconstrictor and pro-adhesion factors such as endothelin-1, angiotensin II, and thromboxanes 4 (Figure 1). These changes lead to increased vascular tone, inflammatory cell and platelet adhesion, and proliferation of the media smooth muscle, which increase the occurrence of thrombosis and vascular occlusion. 3,4 Because of its central role in the pathogenesis of cardiovascular disease, the endothelium is an attractive therapeutic target for cardiovascular disease. 5 Genetic modulation of endothelial function may offer new opportunities to modify the course of common cardiovascular diseases such as hypertension, atherosclerosis, thrombosis, and ischemic artery disease, whereas the availability of endothelial progenitor cells (EPC) 6 may allow the design of cell-based strategies for rescue of ischemic tissue and rep...