Immunotherapy of cancer has deservedly gained much attention in the past few years and is likely to continue to advance and become a fundamental cancer treatment. While vaccines, chimeric antigen receptor (CAR) T cells and checkpoint blockade have received the lion’s share of the attention, an important direct role for gene transfer as an immunotherapy is emerging. For example, oncolytic viruses induce immunogenic cell death, thus liberating both antigens and the signals that are necessary for the activation of antigen-presenting cells, ensuring stimulation of an adaptive response. In another example, transfer of prodrug converting enzymes, such as the herpes simplex virus-thymidine kinase (HSV-tk) gene or the cytosine deaminase gene, has been shown to promote an immune response, thus functioning as immunotherapies. Alternatively, our own work involves the use of nonreplicating viral vectors for the simultaneous delivery of gene combinations that promote both cell death and an immune response. In fact, our gene transfer approach has been applied as a vaccine, immunotherapy or in situ gene therapy, resulting in immunogenic cell death and the induction of a protective immune response. Here, we highlight the development of these approaches both in terms of technical advances and clinical experience.