Recombinant viral vectors such as adenovirus and adenovirus-associated virus have been used widely as vehicles for gene therapy applications because of the high efficiency with which they transfer genes into a wide spectrum of cells in vivo. However, enthusiasm for the use of viral vectors in gene therapy has been tempered by significant problems of attendant host cellular and humoral immune responses that limit their safety and efficacy in vivo. Advances in immunology have suggested a crucial role for the innate immune system in the induction of immune responses to viruses. Thus, a better understanding of the mechanisms by which the host's innate immune system recognizes viruses and viral vectors will help in the design of effective strategies to improve the outcome of viral vector-mediated gene therapy. In this review we first discuss our current understanding of innate immune recognition of viruses in general, and then focus on the innate immune responses to viral vectors for gene therapy.