The ability of small interfering RNA (siRNA) to mediate gene-specific post-transcriptional silencing in mammalian cells will undoubtedly revolutionise functional genomics, as well as drug target identification and validation. Furthermore, there is widespread excitement that siRNA itself might prove useful in the clinical setting. For those wishing to develop siRNA as a therapeutic agent, the most difficult obstacle to overcome will be delivery. Recently, several breakthroughs have highlighted viruses as excellent vehicles for siRNA delivery. Retroviruses, the transgene-delivery vector of choice for many experimental gene therapy studies, have been engineered to deliver and stably express therapeutic siRNA within cells, both in vitro and in vivo. These findings are important milestones for the development of siRNA as a gene therapy for treatment of viral infections, cancer, autoimmune syndromes and numerous genetic disorders. This review describes the development of retroviral siRNA vectors, highlights proof-of-concept experiments demonstrating their therapeutic efficacy and explores therapeutic targets particularly suitable for retroviral-mediated gene silencing.