Recombinant adenovirus-associated (rAAV) vectors due to their ease of construction, wide tissue tropism, and lack of pathogenicity remain at the forefront for long-term gene replacement therapy. In spite of very encouraging preclinical results, clinical trials were initially unsuccessful; expression of the rAAV vector-delivered therapeutic protein was transient. Loss of expression was linked to an expansion of AAV capsid-specific T-cell responses, leading to the hypothesis that rAAV vectors recall pre-existing memory T cells that had been induced by natural infections with AAV together with a helper virus. Although this was hotly debated at first, AAV capsid-specific T-cell responses were observed in several gene transfer trials that used high doses of rAAV vectors. Subsequent trials designed to circumvent these T-cell responses through the use of immunosuppressive drugs, rAAV vectors based on rare serotypes, or modified to allow for therapeutic levels of the transgene product at low, non-immunogenic vector doses are now successful in correcting debilitating diseases.