The development of efficient and safe vectors for gene delivery paved the way for evolution of gene therapy as a new modality for treatment of various inherited disorders and for cancer. The current vectors, viral and non-viral, have their limitations. Innate and adaptive immune responses to vector particles and components may restrict the efficiency of gene transfer and the persistence of expression of the transgene. Results from preclinical studies in animals and more recently data from clinical studies have demonstrated the potential impact of the cellular and the humoral immune response on the therapeutic efficacy. Not only the vector components, but also the transgene products may induce an immune response that negatively affects the therapeutic efficacy. The induction of a cytotoxic T-cell response to transgene-encoded peptides, as well as the production of antibodies directed against secreted proteins have been reported in preclinical and clinical studies, and these may thwart those applications that require long-term expression. Here we will review some of the options to blunt the acquired immune responses to transgene-encoded polypeptides.