Disruptions to protein degradation are an underlying cause or consequence of many diseases, including cancer and neurodegenerative disease. Up to 80% of protein degradation happens through the ubiquitin-proteasome system, yet there are limited treatment options that target this process. A major contribution to the paucity of therapeutics is the complexity of the ubiquitin system. Here, we will focus on the central determinants of the degradative ubiquitin signal, the ubiquitin conjugating enzymes, to understand how they work, and how their activity can be precisely and specifically modulated. Advancing our detailed understanding of how these enzymes contribute to protein degradation will allow the development of more targeted therapeutic approaches.