ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1. This study investigates the role of ZBP1 and TRIF in necroptosis in mice with deficiencies in caspase-8 and TNFR1. Necroptosis is a form of cell death mediated by RIPK3 and MLKL, which occurs when caspase-8 is inhibited. The study used immunohistochemistry (IHC) and in situ hybridization (ISH) to characterize the expression of RIPK1, RIPK3, MLKL, and ZBP1 in mouse tissues. These proteins were co-expressed in most immune cell populations, endothelial cells, and many barrier epithelia. ZBP1 was expressed in many immune populations but had more variable expression in epithelia compared to RIPK1, RIPK3, and MLKL. ZBP1 expression was elevated in Casp8-/- Tnfr1-/- embryos before they succumbed to necroptosis around embryonic day 15. ZBP1 contributed to this embryonic lethality because Casp8-/- Tnfr1-/- Zbp1-/- mice survived until after birth. Necroptosis mediated by TRIF contributed to the demise of Casp8-/- Tnfr1-/- Zbp1-/- pups in the perinatal period. However, Casp8-/- Tnfr1-/- Trif-/- Zbp1-/- mice exhibited autoinflammation and morbidity, typically within 5–7 weeks of being born, which is not seen in other mice. The study found that ZBP1 and TRIF contribute to the embryonic lethality of Casp8-/- Tnfr1-/- mice. ZBP1 is an interferon-stimulated gene, and its expression was significantly elevated in Casp8-/- Tnfr1-/- fetal livers. The results suggest that ZBP1 contributes to the death of Casp8-/- Tnfr1-/- embryos. TRIF also contributed to perinatal lethality in Casp8-/- Tnfr1-/- Zbp1-/- mice. The study highlights the role of ZBP1 and TRIF in necroptosis and their contribution to embryonic and perinatal lethality in mice lacking caspase-8 and TNFR1.ZBP1 and TRIF trigger lethal necroptosis in mice lacking caspase-8 and TNFR1. This study investigates the role of ZBP1 and TRIF in necroptosis in mice with deficiencies in caspase-8 and TNFR1. Necroptosis is a form of cell death mediated by RIPK3 and MLKL, which occurs when caspase-8 is inhibited. The study used immunohistochemistry (IHC) and in situ hybridization (ISH) to characterize the expression of RIPK1, RIPK3, MLKL, and ZBP1 in mouse tissues. These proteins were co-expressed in most immune cell populations, endothelial cells, and many barrier epithelia. ZBP1 was expressed in many immune populations but had more variable expression in epithelia compared to RIPK1, RIPK3, and MLKL. ZBP1 expression was elevated in Casp8-/- Tnfr1-/- embryos before they succumbed to necroptosis around embryonic day 15. ZBP1 contributed to this embryonic lethality because Casp8-/- Tnfr1-/- Zbp1-/- mice survived until after birth. Necroptosis mediated by TRIF contributed to the demise of Casp8-/- Tnfr1-/- Zbp1-/- pups in the perinatal period. However, Casp8-/- Tnfr1-/- Trif-/- Zbp1-/- mice exhibited autoinflammation and morbidity, typically within 5–7 weeks of being born, which is not seen in other mice. The study found that ZBP1 and TRIF contribute to the embryonic lethality of Casp8-/- Tnfr1-/- mice. ZBP1 is an interferon-stimulated gene, and its expression was significantly elevated in Casp8-/- Tnfr1-/- fetal livers. The results suggest that ZBP1 contributes to the death of Casp8-/- Tnfr1-/- embryos. TRIF also contributed to perinatal lethality in Casp8-/- Tnfr1-/- Zbp1-/- mice. The study highlights the role of ZBP1 and TRIF in necroptosis and their contribution to embryonic and perinatal lethality in mice lacking caspase-8 and TNFR1.