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Unresectable recurrent bulky tumors represent a large spectrum of highly complex clinical scenarios that are very challenging to treat. Conventional radiotherapy is ineffective in most of these cases leaving the patients desperate and hopeless. This is due to the large tumor volume and the proximity of the tumor to critical organs and tissues, whose limiting dose constraints make it impossible to apply an ablative dose of radiation, especially if those regions have already been irradiated previously. Additionally, conventional radiotherapy applied to larger treating volumes is associated with lymphopenia, which negatively affects survival. Usually, the only therapeutic option that can be offered to those patients is palliative or best supportive care. That is why improved treatment outcomes for this patient population is needed. Recently, a small group of scientists inspired by the immunomodulatory potential of ionizing radiation moved beyond conventional treatment by giving the radiotherapy quite a different, unconventional form that might overcome the obstacles that make conventional radiotherapy impotent, resulting in an improved therapeutic ratio. This innovative, partial tumor irradiation, adopts different radiobiological mechanisms of action that are based on modulation of anti-tumor immune response. Often, a very dramatic bulky tumor regression, including even complete tumor response, can be observed. The principle behind this innovative approach is to improve the radiotherapy therapeutic ratio by adding an immune-mediated tumor cell killing component to the radiation-mediated tumor cell killing in order to boost the anti-tumor effect. The available literature suggests the safety and effectiveness of this unconventional approach characterized by the high neoadjuvant and immunogenic potential. This lecture will focus on rational, indications and therapeutic potential of novel partial tumor irradiation and its future perspectives.