Treatment of cardiovascular disease by gene therapy remains a promising approach. Preclinical data has proposed the use of gene therapy for diseases as diverse as the prevention of late vein graft failure, in-stent restenosis, myocardial and peripheral ischemia and hypertension. The application of gene therapy is different in each case. Prevention of vein graft failure requires the overexpression of genes that prevent neointimal hyperplasia whereas anti-hypertensive strategies target overexpression of vasodilator genes of knockdown of vasoconstrictors. Viral vectors afford high levels of transgene expression due to their inherent ability to achieve more efficient cell binding, internalisation and nuclear trafficking. However, viral vector delivery is problematic. Adenoviral vectors are required at high dose to mediate sufficient levels of gene delivery, for example in vein grafts and mediate transient gene delivery. It should be noted that the exposure time of target tissue to gene delivery vector is often very short in cardiovascular gene transfer necessitating the use of adenoviral or lentiviral systems. Transduction of cardiovascular cells with adeno-associated viruses (AAV) is relatively poor (perhaps with the exception of cardiac myocytes). Current vector targeting technology is being used to improve gene delivery to vascular tissues in vivo. These include the use of genetic capsid modifications and pseudotyped viruses. Together, these studies imply that gene therapy will provide an attractive route to therapy but further optimisation is required.