Protein ubiquitination and Deubiquitination are reversible processes catalyzed by ubiquitinating enzymes (UBEs) and deubiquitinating enzymes (DUBs). DUBs are categorized into 5 subfamilies: USP, UCH, OTU, MJD, and JAMM. UCHL1, UCHL3, UCHL5/UCH37, and BRCA-1-associated protein-1 (BAP1) belong to the UCH family of DUBs, which all possess a conserved catalytic domain (UCH domain) of about 230 amino acids. Although UCHL1 and UCHL3 are the most closely related UCH family members with about 53% identity, their biochemical properties differ in that UCHL1 binds monoubiquitin and UCHL3 shows dual specificity toward both ubiquitin (Ub) and NEDD8, a Ub-like molecule. UCHL1 (PGP9.5) is a 25 kDa protein; it is highly specific to neurons and to cells of the diffuse neuroendocrine system and their tumors. It comprises >1% of total brain protein but is almost absent from other tissues. It has been implicated both in Parkinson’s disease and in lung cancer.