Scientists have developed and exploited a set of ubiquitin variants that could lead to a better understanding of the way the peptides help manage cellular functions. Ubiquitins regulate cells by a signaling process that is activated via their attachment to key cellular proteins. Deubiquitinating enzymes later remove these ubiquitin tags from the proteins. The enzymes also play a role in some cancers and neurodegenerative, hematologic, and infectious diseases. Inhibitors can be used to study the enzymes’ roles, but only a few weak inhibitors have been identified. In Science, Sachdev S. Sidhu of the University of Toronto and coworkers report that they have identified potent deubiquitinating enzyme inhibitors by screening a combinatorial library of ubiquitin-like compounds (DOI: 10.1126/science.1230161). They also screened the library to find agents that inhibit enzymes that conjugate ubiquitins to proteins or recognize ubiquitin tags. The ubiquitin variants “will serve as useful genetic probes to assess and modulate ubiquitin system function in vivo,” they write.