SUMOs are Small Ubiquitin-like Modifiers that are covalently conjugated to extensive sets of target proteins in cells to regulate their activity. A properly functioning sumoylation system is essential for eukaryotic life. The system comprises a set of conjugating enzymes known as E1, E2 and E3s and a set of deconjugating enzymes known as SENPs. Three mammalian SUMO family members have been identified, SUMO-1, SUMO-2 and SUMO-3. Sumoylation is involved in virtually all cellular processes including transcription, DNA damage response pathways, transport, ribosome biogenesis, pre-mRNA splicing, RNA editing and the cell cycle. Similar to ubiquitin, SUMOs form chains via internal sumoylation sites present in the flexible N-terminal parts of SUMO-2, SUMO-3 and the single SUMO family member in S. cerevisiae SMT3. SUMO-interacting proteins bind to mono- or poly-sumoylated proteins in a non-covalent manner to regulate the fate of sumoylated proteins. Sumoylation acts in concert with other post-translational modifications such as phosphorylation, acetylation and ubiquitination. In addition to SUMOs, the ubiquitin family consists of ISG15, NEDD8, ATG8, ATG12, FUBI, URM1, UFM1, FAT10, HUB1 and PUP. These protein modifiers play important roles in immunity, autophagy, ribosome biogenesis and other processes.