The accessibility, distribution, and mass of endothelial cells make this cell type an ideal target for in vivo gene transfer. Genetic modification of endothelial cells has been contemplated for a variety of therapeutic purposes, including induction of angiogenesis, prevention of restenosis following angioplasty, suppression of vessel growth in tumors, and as a source of therapeutic proteins for treatment of hereditary or acquired disorders. In targeting endothelial cells for gene transfer, the complex physiology of these cells must be taken into account. Optimizing gene transfer to endothelial cells by working in concert with endothelial cell physiology may lead to a significant decrease in dose of vector required to achieve a therapeutic result, thus increasing the safety and utility of this approach.