Activation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) controls tumor necrosis factor receptor (TNFR)- and pattern recognition receptors-mediated apoptosis, necroptosis and inflammatory pathways. RIPK1 activity is regulated post-translationally by ubiquitylation and phosphorylation events, as well as by caspase-8 (CASP8)-mediated cleavage. CASP8 facilitates the cleavage of human and mouse RIPK1 after residues D324 and D325, respectively and prevents caspase-8-dependent apoptosis and RIPK1:RIPK3-dependent necroptosis (Lin Y et al. 1999; Hopkins-Donaldson S et al. 2000; Newton K et al. 2019; Zhang X et al. 2019; Lalaoui N et al. 2020). The dominantly inherited mutations D324N, D324H, D324V and D324Y in RIPK1 prevent CASP8 from cleaving the mutated protein, thereby promoting activation of RIPK1 and leading to an autoinflammatory response in humans (Tao P et al. 2020; Lalaoui N et al. 2020).