There is no doubt that protein phosphorylation is the most extensively studied post-translational modification, and it is well established that a plethora of cellular activities are regulated by the interplay between kinases and phosphatases. However, in recent years, ubiquitylation has emerged as a close runner-up. Since its discovery as a degradation signal, numerous studies have shown that the covalent attachment of ubiquitin moieties to proteins regulates various cellular processes, including DNA repair, the cell cycle and receptor endocytosis. In this Minifocus, we present a collection of articles that examine a number of these functions in detail. The first part of this collection begins with a comprehensive overview of the roles that ubiquitin and SUMO have in the regulation of DNA repair in Helle Ulrich's Cell Science at a Glance poster article (p. 249). In their Commentary, Annamaria Mocciaro and Michael Rape (p. 255) highlight the emerging mechanisms in ubiquitin-dependent cell cycle control. Kaisa Haglund and Ivan Dikic (p. 265) summarise the roles that ubiquitylation has in regulating the endocytic pathways of receptor tyrosine kinases in a Commentary. Finally, in their Commentary on page 277, Michael Clague, Judy Coulson, and Sylvie Urbé discuss what is currently known about the enzymes that reverse this post-translational modification, the deubiquitylases.