In mammalian cells, the small ubiquitin-like modifier (SUMO) family contains four isoforms (SUMO1, SUMO2, SUMO3, and SUMO4). SUMO2 and SUMO3 are almost identical, with only a difference in three amino acid residues. SUMO1 shares 48% identity with SUMO2/31. SUMO4 is about 85% identical to SUMO2/3, but it is unclear whether SUMO4 can be conjugated to substrates2. Similar to ubiquitination, SUMOylation requires a three enzymes system (E1, E2, and E3) to conjugate SUMO covalently to target substrates. Briefly, SUMO is first activated by the SUMO E1 activating heterodimeric enzyme SAE1/SAE2 by adenylation in an ATP-dependent reaction. The activated SUMO is then transferred to the SUMO E2 conjugating enzyme UBC9 and finally conjugated to a target protein by a SUMO E3 ligase (e.g., PIAS family members, Ran binding protein 2). The covalently linked SUMO can be removed by sentrin-specific proteases (SENPs), a process known as deSUMOylation3 (Fig. 1). SUMOylation is an essential post-translational modification (PTM) that regulates the activity, subcellular localization, stability, and functions of target proteins and thereby modulates almost all major cellular pathways4. Therefore, it is not surprising that many diseases are associated with dysregulation of SUMOylation. In this newsletter, the roles of SUMOylation/deSUMOylation in cancer are discussed.