Over 40 years since its discovery, the diversity and consequences of protein ubiquitylation continue to expand. Virtually every biological process is regulated at some level by protein ubiquitylation. While most post-translational modifications encompass a single type of chemical linkage, Ubiquitin attachment to a substrate can occur via a growing number of chemical linkages, creating an elaborate and diverse universe of signals. I will discuss what we know about how these modifications are carried out by the ubiquitylation machinery and what remains to be understood.