Caspase-8 and FLIP form a proteolytically active complex that inhibits RIPK3-dependent necrosis, preventing cell death during development. Caspase-8 has dual roles in apoptosis and cell survival, while FLIP, which resembles caspase-8 but lacks a catalytic site, antagonizes apoptosis by inhibiting RIPK3. Genetic ablation of caspase-8 leads to embryonic lethality, but this is rescued by RIPK3 ablation, indicating that caspase-8 suppresses RIPK3-dependent necrosis. Caspase-8-deficient mice lacking RIPK3 display normal development and resistance to CD95 ligation, suggesting that caspase-8's protective role is to inhibit RIPK3-dependent necrosis. The caspase-8-FLIP complex prevents RIPK3-dependent necrosis without inducing apoptosis, as shown by in vitro experiments where non-cleavable caspase-8 with FLIP was enzymatically active. FLIP is essential for caspase-8's protective function, as its absence leads to cell death in the absence of caspase-8. Caspase-8-FLIP heterodimers prevent stable association of FADD, RIPK1, and RIPK3, thereby inhibiting necrotic death. These findings suggest that the caspase-8-FLIP complex is crucial for suppressing RIPK3-dependent necrosis during development and immune cell proliferation. The study also shows that FLIP is a key component of the protective effect, and its role in NF-κB signaling may be important for immune cell survival. The results highlight the importance of the caspase-8-FLIP complex in preventing RIPK3-dependent necrosis without promoting apoptosis.Caspase-8 and FLIP form a proteolytically active complex that inhibits RIPK3-dependent necrosis, preventing cell death during development. Caspase-8 has dual roles in apoptosis and cell survival, while FLIP, which resembles caspase-8 but lacks a catalytic site, antagonizes apoptosis by inhibiting RIPK3. Genetic ablation of caspase-8 leads to embryonic lethality, but this is rescued by RIPK3 ablation, indicating that caspase-8 suppresses RIPK3-dependent necrosis. Caspase-8-deficient mice lacking RIPK3 display normal development and resistance to CD95 ligation, suggesting that caspase-8's protective role is to inhibit RIPK3-dependent necrosis. The caspase-8-FLIP complex prevents RIPK3-dependent necrosis without inducing apoptosis, as shown by in vitro experiments where non-cleavable caspase-8 with FLIP was enzymatically active. FLIP is essential for caspase-8's protective function, as its absence leads to cell death in the absence of caspase-8. Caspase-8-FLIP heterodimers prevent stable association of FADD, RIPK1, and RIPK3, thereby inhibiting necrotic death. These findings suggest that the caspase-8-FLIP complex is crucial for suppressing RIPK3-dependent necrosis during development and immune cell proliferation. The study also shows that FLIP is a key component of the protective effect, and its role in NF-κB signaling may be important for immune cell survival. The results highlight the importance of the caspase-8-FLIP complex in preventing RIPK3-dependent necrosis without promoting apoptosis.