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Necroptosis induction in vitro often requires caspase-8 (Casp8) inhibition by zVAD because pro-Casp8 cleaves RIP1 to disintegrate the necrosome. It has been unclear how the Casp8 blockade of necroptosis is eliminated naturally. Here, we show that pro-Casp8 within the necrosome can be inactivated by phosphorylation at Thr265 (pC8T265). pC8T265 occurs in vitro in various necroptotic cells and in the cecum of TNF-treated mice. p90 RSK is the kinase of pro-Casp8. It is activated by a mechanism that does not need ERK but PDK1, which is recruited to the RIP1-RIP3-MLKL-containing necrosome. Phosphorylation of pro-Casp8 at Thr265 can substitute for zVAD to permit necroptosis in vitro. pC8T265 mimic T265E knockin mice are embryonic lethal due to unconstrained necroptosis, and the pharmaceutical inhibition of RSK-mediated pC8T265 diminishes TNF-induced cecum damage and lethality in mice by halting necroptosis. Thus, phosphorylation of pro-Casp8 at Thr265 by RSK is an intrinsic mechanism for passing the Casp8 checkpoint of necroptosis. • Phosphorylation of pro-caspase-8 at Thr265 releases the blockade of necroptosis • RSK phosphorylates pro-caspase-8 at Thr265 in the necrosome • PDK1 activates RSK by an ERK-independent mechanism to promote necroptosis • RSK inhibition protects mice from TNF-induced cecum injury and lethality An intrinsic mechanism—RSK, activated by TNF via PDK1—for overcoming necroptosis blockade is revealed by Yang et al. that phosphorylates pro-caspase-8 at Thr265 within the necrosome to inactivate pro-caspase-8. [ABSTRACT FROM AUTHOR]