Despite significant advances in prevention, coronary artery disease remains the leading cause of death in the Western world. Surgical bypass and angioplasty are the primary interventional therapies but they are limited by the problems of restenosis and graft occlusions. Natural response to vascular occlusion involves the formation of collateral vessels that bypass obstructions, but they are often inefficient in relieving ischemia. Vascular gene transfer offers a promising new approach to solve these problems. Its potential has been shown in animal models and in first human trials using vascular endothelial growth factor, fibroblast growth factor, and E2F cell-cycle transcription factor decoy. However, further basic research on gene transfer vectors, gene delivery techniques, and identification of effective treatment genes is needed to improve the efficacy and safety of human vascular gene therapy.