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The programmed cell death machinery exhibits surprising flexibility, capable of crosstalk and non-apoptotic roles. Much of this complexity arises from the diverse functions of caspase-8, a cysteine-aspartic acid protease typically associated with activating caspase-3 and - 7 to induce apoptosis. However, recent research has revealed that caspase-8 also plays a role in regulating the lytic gasdermin cell death machinery, contributing to pyroptosis and immune responses in contexts such as infection, autoinflammation, and T-cell signalling. In mice, loss of caspase-8 results in embryonic lethality from unrestrained necroptotic killing, while in humans caspase-8 deficiency can lead to an autoimmune lymphoproliferative syndrome, immunodeficiency, inflammatory bowel disease or, when it can't cleave its substrate RIPK1, early onset periodic fevers. This review focuses on non-canonical caspase-8 signalling that drives immune responses, including its regulation of inflammatory gene transcription, activation within inflammasome complexes, and roles in pyroptotic cell death. Ultimately, a deeper understanding of caspase-8 function will aid in determining whether, and when, targeting caspase-8 pathways could be therapeutically beneficial in human diseases., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Ltd. All rights reserved.)