The article discusses the regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes (DUBs). DUBs are proteases that remove ubiquitin from proteins, playing key roles in the ubiquitin pathway. The human genome encodes nearly 100 DUBs, belonging to five families: UCH, USP, OTU, Josephin, and JAMM. Most DUBs are cryptic, requiring substrate or scaffold protein binding to achieve catalytic activity. DUBs have multiple domains that modulate substrate specificity, protein-protein interactions, and cellular localization. They associate with binding partners and multi-protein complexes that modulate activity and substrate specificity. Quantitative studies, genetic studies, and RNAi have provided new insights into DUB function in yeast and humans. This review discusses the regulation of DUB activity, their roles in various cellular processes, and specific examples from studies of protein degradation, DNA repair, chromatin remodeling, cell cycle regulation, endocytosis, and signaling kinases. DUBs are modular, containing catalytic domains and additional ubiquitin-binding domains and protein-protein interaction domains. They are involved in various cellular functions, including cell cycle regulation, proteasome- and lysosome-dependent protein degradation, gene expression, DNA repair, kinase activation, microbial pathogenesis, and more. DUBs are regulated by post-translational modifications such as phosphorylation, ubiquitination, and sumoylation. DUB activity is often cryptic and requires conformational changes to achieve catalytic activity. DUBs are involved in the processing of polyubiquitin chains and the regulation of ubiquitin levels. DUBs are also involved in the regulation of histone ubiquitination, which is important for transcription, chromatin remodeling, and gene silencing. The article highlights the importance of DUBs in various cellular processes and their roles in disease, including cancer and neurological disorders.The article discusses the regulation and cellular roles of ubiquitin-specific deubiquitinating enzymes (DUBs). DUBs are proteases that remove ubiquitin from proteins, playing key roles in the ubiquitin pathway. The human genome encodes nearly 100 DUBs, belonging to five families: UCH, USP, OTU, Josephin, and JAMM. Most DUBs are cryptic, requiring substrate or scaffold protein binding to achieve catalytic activity. DUBs have multiple domains that modulate substrate specificity, protein-protein interactions, and cellular localization. They associate with binding partners and multi-protein complexes that modulate activity and substrate specificity. Quantitative studies, genetic studies, and RNAi have provided new insights into DUB function in yeast and humans. This review discusses the regulation of DUB activity, their roles in various cellular processes, and specific examples from studies of protein degradation, DNA repair, chromatin remodeling, cell cycle regulation, endocytosis, and signaling kinases. DUBs are modular, containing catalytic domains and additional ubiquitin-binding domains and protein-protein interaction domains. They are involved in various cellular functions, including cell cycle regulation, proteasome- and lysosome-dependent protein degradation, gene expression, DNA repair, kinase activation, microbial pathogenesis, and more. DUBs are regulated by post-translational modifications such as phosphorylation, ubiquitination, and sumoylation. DUB activity is often cryptic and requires conformational changes to achieve catalytic activity. DUBs are involved in the processing of polyubiquitin chains and the regulation of ubiquitin levels. DUBs are also involved in the regulation of histone ubiquitination, which is important for transcription, chromatin remodeling, and gene silencing. The article highlights the importance of DUBs in various cellular processes and their roles in disease, including cancer and neurological disorders.