Reversible post-translational modification is a rapid and efficient system to control the activity of pre-existing proteins. Modifiers range from small chemical moieties, such as phosphate groups, to proteins themselves as the modifier. The patriarch of the protein modifiers is ubiquitin which plays a central role in protein degradation and protein targeting. Over the last 10 years, the ubiquitin family has expanded to include a variety of ubiquitin-related small modifier proteins that are all covalently attached to a lysine residue on target proteins via series of enzymatic reactions. Of these newly discovered ubiquitin-like proteins, the SUMO family has gained prominence as a major regulatory component that impacts numerous aspects of cell growth and differentiation. Unlike ubiquitinylation which often leads to protein turn over, sumoylation performs a variety of functions such as altering protein stability, protein trafficking, protein-protein interaction, and protein activity. This chapter will introduce the basic properties of SUMO proteins and the general tenets of sumoylation. Springer Science+Business Media B.V. 2009.