The ubiquitin-mediated protein degradation pathway exerts a wide spectrum of effects and modulates a variety of biological processes including cell cycle progression, transcriptional regulation, signal transduction, antigen presentation, apoptosis (or programmed cell death), oncogenesis, preimplantation, and DNA repair. Recently, the importance of deubiquitination mechanism has been emerged as an essential regulatory step to control these cellular mechanisms for homeostasis. Even though a number of deubiquitinating enzymes have recently been isolated, relatively little is known about their substrates and biological functions. Identified from yeast to human, deubiquitinating (DUB) enzymes are classified into the ubiquitin C-terminal hydrolase (UCH), the ubiquitin-specific processing proteases (UBP or USP), Jab1/Pad1/MPN domain containing metallo-enzymes (JAMM), Otu domain ubiquitin-aldehyde binding proteins (OTU), and Ataxin-3/Josephin domain containing proteins (Ataxin-3/Josephin). Several members of a novel DUB subfamily induced by cytokines in murine lymphocytes have recently been identified. In addition, human DUB enzyme DUB-3, highly homologous to USP17 and induced by cytokines interleukin (IL)-4 and IL-6, has been recently isolated and showed that it has significant homology to the known murine DUB subfamily members. Interestingly, both murine DUB and human USP17 subfamily members are localized and clustered on murine chromosome 7 and on human chromosomes 4 and 8, respectively. This review introduces the reader to provide a great understanding of cytokine-inducible DUB enzymes in both mouse and human, and new insights into DUB subfamily members.