Resistance to therapy is a major obstacle to cancer treatment. It may exist from the beginning, or it may develop during therapy. The review focusses on oncolytic Newcastle disease virus (NDV) as a biological agent with potential to break therapy resistance. This avian virus combines, upon inoculation into non-permissive hosts such as human, 12 described anti-neoplastic effects with 11 described immune stimulatory properties. Fifty years of clinical application of NDV give witness to the high safety profile of this biological agent. In 2015, an important milestone was achieved, namely the successful production of NDV according to Good Manufacturing Practice (GMP). Based on this, IOZK in Cologne, Germany, obtained a GMP certificate for the production of a dendritic cell vaccine loaded with tumor antigens from a lysate of patient-derived tumor cells together with immunological danger signals from NDV for intracutaneous application. This update includes single case reports and retrospective analyses from patients treated at IOZK. The review also presents future perspectives, including the concept of in situ vaccination and the combination of NDV or other oncolytic viruses with checkpoint inhibitors.