A comprehensive review is offered of recent fundamental and clinical research, much of it by the authors, into the mechanisms and applications of neovascularization, a term encompassing both angiogenesis, where mature endothelial cells (ECs) leave the basement membrane and proliferate as sprouts from parental vessels, and vasculogenesis, where bone marrow-derived endothelial progenitor cells (EPCs) circulate to ischemic sites and differentiate into mature ECs. EPCs act as a substrate for growth factors, notably vascular endothelial growth factor (VEGF), released endogenously in response to tissue ischemia or administered exogenously for therapeutic neovascularization in subjects (elderly, diabetics) unable to upregulate their cytokine expression. Phase 1 trials in critical limb ischemia with intramuscular injection of naked plasmid DNA encoding the 165-amino-acid isoform of human VEGF show increased gene product expression, magnetic resonance angiography evidence of improved blood flow, and concomitantly reduced rest pain. Results are similar in class III-IV angina where electromechanical mapping evidence of hibernating myocardium salvage is associated with decreased anginal episodes. VEGF also reverses peripheral neuropathy via its ability to preserve the vasa nervorum. Optimal therapeutic strategy comprises stimulation of the EPC substrate combined with VEGF administration. No potential adverse effects of neovascularization—increased malignancy, proliferative retinopathy—have yet been reported...