SUMO (small ubiquitin-related modifier) family proteins are not only structurally but also mechanistically related to ubiquitin in that they are posttranslationally attached to other proteins. As ubiquitin, SUMO is covalently linked to its substrates via amide (isopeptide) bonds formed between its C-terminal glycine residue and the epsilon-amino group of internal lysine residues. The enzymes involved in the reversible conjugation of SUMO are similar to those mediating the ubiquitin conjugation. Since its discovery in 1996, SUMO has received a high degree of attention because of its intriguing and essential functions, and because its substrates include a variety of biomedically important proteins such as tumor suppressor p53, c-jun, PML and huntingtin. SUMO modification appears to play important roles in diverse processes such as chromosome segregation and cell division, DNA replication and repair, nuclear protein import, protein targeting to and formation of certain subnuclear structures, and the regulation of a variety of processes including the inflammatory response in mammals and the regulation of flowering time in plants.