ABSTRACTCYLD lysine 63 deubiquitinase (CYLD) is a ubiquitin hydrolase with important roles in immunity and cancer. CompleteCYLDablation, truncation and expression of alternate isoforms, including short CYLD, drive distinct phenotypes and offer insights into CYLD function in inflammation, cell death, cell cycle progression and cell transformation. Research in diverse model systems has shown that these are mediated via CYLD regulation of cellular pathways including the NF-κB, Wnt and TGF-β pathways. Recent biochemical advances and models have offered new insights into the regulation and function of CYLD. In addition, recent discoveries of gain-of-function germline pathogenicCYLDvariants in patients with a neurodegenerative phenotype contrast with the more widely known loss-of-function mutations seen in patients with CYLD cutaneous syndrome and with sporadic cancers. Here, we provide a current review of mechanistic insights into CYLD function gained fromCYLDanimal models, as well as an update on the role of CYLD in human disease.