SUMO (small ubiquitin-related modifier), a member of the ubiquitin-like protein family, regulates diverse cellular functions of a variety of target proteins including transcription, DNA repair, nucleocytoplasmic trafficking and chromosome segregation. SUMO precursor proteins undergo cleavage of the residues after the “GG” region by SUMO-specific proteases in maturation. This cleavage of the precursor is a prerequisite for subsequent sumoylation. The sentrin-specific (or SUMO-specific) protease (SENP) proteins belong to the peptidase C48 family and include SENP1-3 and SENP5-8. SENP1, SENP2 and SENP3 degrade UBL1 and SMT3H2 conjugates and subsequently release the monomers from sumoylated substrates. HIPK2 is a desumoylation target for SENP1 which shuttles between the cytoplasm and the nucleus. Mutation analyses reveal that SENP1 contains the nuclear export sequence (NES) within the extreme carboxyl-terminal region, and SENP1 is exported to the cytoplasm in a NES-dependent manner. SENP2 has been implicated as a downregulator of CTNNB1 levels and may therefore be a modulator of the Wnt pathway. SUMO protease SENP3 reverses the sumoylation of MEF-2 to augment its transcriptional and myogenic activities. SENP5 localizes to the nucleolus and preferentially processes SUMO-3.