While proteasome inhibitors are now well-established research tools and chemotherapeutics, proteasome activators are much less explored. In this issue of Cell Chemical Biology, in a study from the groups of Berkers and Ovaa (Leestemaker et al., 2017), a chemical screen was used to identify a p38 MAPK inhibitor as a proteasome activator. This compound furthermore enhanced clearance of protein aggregates, thereby implicating alternative chemotherapeutic options for treating neurodegenerative diseases.