Although crucial for the protection of the human body against various insults, inflammation needs to be tightly regulated to avoid the pathological consequences resulting from an insufficient/excessive or chronic inflammatory response. Inflammation and cell death are interconnected cellular processes directly influencing each other. RIPK1 emerged as an essential signalling node downstream of several immune receptors, where it functions as an adaptor molecule that controls gene activation and as a kinase promoting cell death. The molecular mechanism regulating the switch from “ro-survival”RIPK1 to “ro-death”RIPK1 is currently unknown. In addition, the involvement of RIPK1 kinase-dependent death in inflammatory and infectious diseases is currently unclear. This research proposal aims at gaining a better understanding of RIPK1 biology by defining the molecular nature of the RIPK1 cell death checkpoint and by revealing its physiological relevance in models of infection and disease. The research proposal integrates studies performed at the biochemical, cellular and organism levels. We believe that the knowledge acquired on RIPK1 with this research proposal will help identifying disorders in which RIPK1 kinase inhibitors may provide a therapeutic advantage.