Cancer patients often exhibit immunosuppression that is caused by the expanding tumor mass. This fact has severely compromised many efforts to develop effective cancer vaccines in the past. However, a new generation of immunotherapies takes focus on both activating the effector cells of the immune system as well as reverting the immunosuppression. This two-step process has lead to impressive anti-tumor effects both in experimental settings as well as in initial clinical trials. With new and powerful techniques for genetic engineering, the transfer of immunostimulating genes has gained interest. Genetic engineering of the tumor micromilieu has, for example, shown to be an effective means for breaking tumor-induced immunosuppression in an experimental model of bladder cancer. Genetic engineering can also be used to modify the immune effector cells to efficiently target tumor cells and to simultaneously resist immune inhibition. This review will discuss the immunological status of cancer patients with focus on T regulatory cells and their inhibitory cytokines as well as offer a survey of novel immune strategies for cancer gene therapy.