In this issue of Circulation, Baumgartner et al1 report a significant advance in angiogenic gene therapy. The authors induced collateral neovascularization in 10 critically ischemic limbs in 9 patients by the intramuscular gene transfer of naked plasmid DNA encoding the 165-amino-acid isoform of the human angiogenic protein, vascular endothelial growth factor (phVEGF165). The plasmid DNA was injected directly into the muscle of ischemic limbs. Anatomic and functional efficacy was demonstrated by increased serum levels of VEGF, improved hemodynamic measurements and angiographic evaluation, reduced pain, increased healing of ischemic ulcers, limb salvage, and immunohistochemical evidence of proliferating endothelial cells in tissue specimens. The authors emphasize that this is the first medical therapy to achieve an increase in limb perfusion that is equivalent to or greater than successful surgical or percutaneous intervention.