The ability to deliver genes, and hence therapeutic gene over-expression site-specifically in vivo remains the major challenge for research in the field. The obligate need to target transgene expression safely, efficiently, and selectively has become increasingly evident as a result of recent events in the clinical setting. The endothelium represents an important target for gene delivery given its fundamental role in the physiology and pathophysiology of many diseases. Recently, studies demonstrating the ability to target viral vectors to the endothelium have been reported. In this review, we discuss progress to date and highlight those areas still requiring further investigation and validation.