The discovery of the process of small ubiquitin-like modifier (SUMO)-mediated post-translational modification of targets (SUMOylation) in early 1990s proved to be a significant step ahead in understanding mechanistic regulation of proteins and their functions in diverse life processes at the cellular level. The critical step in reversing the SUMOylation pathway is its ability to be dynamically deSUMOylated by SUMO/sentrin-specific protease (SENP). This review is intended to give a brief introduction about the process of SUMOylation, different mammalian deSUMOylating enzymes with special emphasis on their regulation of ribosome biogenesis at the molecular level, and its emerging roles in mitochondrial dynamics that might reveal usefulness of SENPs for therapeutic applications.