Gene therapy has the potential to provide minimally invasive and long-term treatment for many inherited disorders that otherwise have poor prognoses and limited treatment options. The sustained therapeutic correction of genetic disease by viral gene transfer has been accomplished in patients with severe immune deficiencies, or by the transduction of an immune privileged site for the treatment of ocular disease. For other diseases and target tissues, immune responses to vectors or transgene products often present major obstacles for therapy. Innate and adaptive immunity, sometimes including pre-existing or memory responses, may contribute by varying degrees to immune-mediated rejection and immunotoxicity. This review provides an overview of the immune responses to in vivo gene transfer with the most commonly used viral gene therapy vectors, and discusses strategies and protocols employed in evading the immune system in order to provide optimal gene therapy.