Tumor necrosis factor (TNF) is a cytokine with an extremely strong anticancer potential, especially when it is combined with other antitumor drugs, such as melphalan or Interferon-gamma (IFNg). Administration of TNF/IFNg to tumor bearing animals leads to complete regression of all solid tumors tested so far. The use of TNF in patients is limited to loco-regional treatments, because TNF/IFNg also leads to inflammation, shock and death. This toxicity has discouraged many researchers in the belief that TNF/IFNg might breakthrough as a universal and safe cancer treatment. However, we recently obtained data showing that tumor killing and host killing can be uncoupled. Indeed, we found that mice that express only one functional copy of TNFRp55 are extremely resistant to TNF toxicity and can survive the high doses needed for efficient tumor regression and that these findings can be partially translated to a therapeutic setting. We want to explore several aspects of these findings in more detail (mechanisms, therapeutic niche, etc.) and even expand the therapeutic value of TNF further. Besides its impressive anti-tumor effects, TNF is also a well-known mediator in several pathologies (e.g. arthritis, psoriasis, asthma, inflammatory bowel disease). We want to explore whether downregulation or inhibition of TNFRp55 has a therapeutic future in these TNF-mediated diseases. Finally, more research is planned to optimize therapeutic down-regulation and/or inhibition of the TNFRp55.