Gene-modified T cells were the first gene therapy tool used in clinical gene transfer trials. After the first applications in immunodeficiency diseases, T cell gene therapy has been extended to HIV infection and cancer. The primary obstacle to successful T cell gene therapy has proven to be the robust immune responses elicited by the gene-modified T cells even in severely immunosuppressed patients. The potent antibody and cytotoxic immune responses have interfered with the expression and persistence of the therapeutic transgene. In this review we will address each of the components of T cell gene therapy - culture conditions, vector, and transgene - that have elicited these immune responses and the strategies used to minimize them.