Posttranslational modification by small ubiquitin-like modifier (SUMO) controls diverse cellular processes including transcriptional regulation, nuclear transport, cell-cycle progression, DNA repair, and signal transduction pathway. Sumoylation is a highly dynamic process that is reversed by a family of Sentrin/SUMO-specific proteases (SENPs). Thus, desumoylation process must be important for regulation of the fate and function of SUMO-conjugated proteins as well as SUMOylation process. SENPs catalyze the removal of SUMO from SUMO-conjugated target proteins as well as the cleavage of SUMO from its precursor proteins. Since the first report of yeast desumoylating enzymes, many studies have revealed the structural and cellular biological properties of SENP family. This review focuses on the specificity of the SENPs' catalytic activities with regard to SUMO isoforms and their emerging roles as cellular regulators.