Broadly defined, gene therapy is the use of recombinant genetic materials (DNA or RNA) to achieve a therapeutic benefit. In this context, gene therapeutics can be applied to organs or cells in vivo or to tissue removed ex vivo and subsequently returned back to the patient after the cells have been genetically modified. Early gene therapeutics were based on the ex vivo paradigm, wherein donated bone marrow hematopoietic cells were engineered to produce adenosine deaminase (ADA), in an attempt to correct the defective native ADA gene and reverse a severe underlying immunodeficiency syndrome (severe combined immunodeficiency syndrome [SCIDS]).1 Subsequently, urologic applications of ex vivo gene therapy have been directed at the immunotherapy of certain malignancies. These strategies have relied on cytokine manipulation of the isolated tumor cells to augment the host immune response when reinjected as a vaccine. In particular, paracrine secretion of certain cytokines (eg, interleukin-2, interferon, granulocyte-macrophage colony-stimulating factor) from explanted, transduced, and then irradiated tumor cells results in stimulation of the professional antigen-presenting cells (dendritic cells) and subsequent activation of cytotoxic T cells against endogenous tumor antigens (Fig. 1). Such a paradigm has been demonstrated for both renal and prostate cancer.2 Although a great deal was learned from these studies, the outcomes have shown only modest responses, due in part to the large numbers of cells required for adequate dosing of the vaccinations. The more recent development of allogeneic vaccinations,3 which provide an inexhaustible source of tumor cells by using immortalized human cells, may provide a solution to this dilemma. In the case of prostate cancer, multiple immunoevasive behaviors have been identified that may allow cancer cells to escape certain aspects of tumor surveillance. In particular, some advanced prostate cancer cells have defective major histocompatibility complex (MHC) I processing.4 Since activated killer T cells localize to prostate cancer cells, which express particular tumor antigens in the context of MHC I expression, this lack of expression hinders cytotoxic T-cell activity. In addition, there is some evidence to suggest that some advanced prostate cancer cells may secrete soluble factors that interfere with T-cell receptor function, resulting in aberrant delta-chain expression and therefore a further diminished cytotoxic T-cell response.5 Methods of circumventing some of these immunoevasive features are being developed, including the use of genetically modified tumor cells that express certain costimulatory molecules (eg, HLA-B7) normally found on antigen-presenting cells.6,7 This approach bypasses an intermediate step in the development of a potent cytotoxic T-cell response and potentially circumvents the difficulty with faulty MHC I processing in prostate cancer cells. Such studies are in their early developmental phases but offer much promise for the immunotherapy of urologic malignancies. Another active area of ex vivo research is the development of dendritic cell therapy. In this case, autologous dendritic cells are harvested and exposed to highly specific polypeptide fragments that are known to be preferentially expressed in the organ of interest. An example of this approach is the “pulsed” exposure of dendritic cells to certain fragments of the prostate-specific membrane antigen. Such “pulsed-dendritic cells” are then redelivered into the patient from whom they were derived. Although these trials have been criticized for study design, a Phase I study of 51 patients with prostate cancer (including control groups) revealed seven partial responses to this type of therapy.8