The synergy of gene therapy and immunotherapy has allowed great progress in the treatment of hematological malignancies. In recent years, T cells engineered to express chimeric antigen receptors (CARs) directed against CD19 have led to unprecedented rates of complete responses in B-cell acute lymphoblastic leukemia, chronic lymphoblastic leukemia, and diffuse large B-cell lymphoma. These remarkable results prompted the Food and Drug Administration approval of Tisagenlecleucel (marketed as Kymriah) and Axicabtagene ciloleucel (marketed as Yescarta), two anti-CD19 CAR-T therapies. However, many challenges remain. Treatment is often associated with cytokine release syndrome and sometimes further leads to neurotoxicity. In addition, many patients may still relapse with a CD19-negative blast or a CD19- positive blast following CAR-T exhaustion and depletion. Furthermore, T-cell responses represent only one of many potentially therapeutic responses, and the genetic manipulation of other immune cells is at a much earlier stage of development. Most importantly, the great potential of immune gene therapy is yet to be manifested in the treatment of solid tumors and autoimmune diseases or in organ transplantations. This special issue of Human Gene Therapy features selected publications trying to tackle the many remaining hurdles using diverse cutting-edge technologies.