A clue to a drug's neurotoxicity? The drug BIA 10-2474 inhibits fatty acid amide hydrolase (FAAH), a lipase that degrades a specific endocannabinoid. On the basis of this activity, BIA 10-2474 was being developed as a potential treatment for anxiety and pain. In a phase 1 trial of the drug, one subject died, and four others suffered brain damage. As an initial step in investigating whether inhibition of off-target proteins by BIA 10-2474 might contribute to its clinical neurotoxicity, van Esbroeck et al. used activity-based proteomic assays to identify proteins targeted by the drug. Studying human cells and brain samples from subjects not associated with the trial, they found that BIA 10-2474 targeted several different lipases in addition to FAAH. It also substantially altered lipid metabolism in cultured neurons. Science , this issue p. 1084