Over a decade ago, a small cellular protein of 12 kDa, with 18% homology to the well-known ubiquitin protein, was co-discovered and termed Small Ubiquitin-like Modifier, or SUMO. Sumoylation is a post-translational modification that utilizes SUMO as the modifier group covalently attached to target substrates. This state-of-the art review on the sumoylation system deals with protein modification as it pertains to regulation of diverse cellular functions. Each chapter has been written by a leading researcher and covers the role of sumoylation in fundamental biochemical activities (transcription, RNA processing, chromatin remodelling, DNA repair, nucleocytoplasmic transport, ion channel regulation, and metabolic pathways). The text also examines the part sumoylation plays in critical cellular processes such as mitosis, meiosis, differentiation, senescence, and apoptosis. Lastly, the emerging role of sumoylation in specific diseases, including cancer and diabetes as well as neurodegenerative ones, is explored with an emphasis on defining molecular mechanisms that may provide new targets for treatment or prevention. While SUMO was discovered more than 10 years ago, this is still a relatively young field, and much remains to be discovered about the biochemical and biological properties of this modification system. In just the last few years, it has become clear that sumoylation modifies hundreds of cellular proteins, and there has been increased appreciation for the breadth of cellular functions that are impacted by this post-translational modification.