A clickable inhibitor reveals context-dependent autoactivation of p90 RSK. Cohen et al. (p 156) generated fmk-pa, a potent inhibitor of the p90 ribosomal S6 kinases RSK1 and RSK2. The authors used click chemistry to show specific and irreversible modification of RSKs in mammalian cells. RSKs are activated by the MEK-ERK signal transduction pathway through phosphorylation of the C-terminal kinase domain (CTD), which goes on to phosphorylate and activate the N-terminal kinase domain (NTD). Using their inhibitor, the authors found evidence for an unidentified kinase that bypasses RSK CTD activity. The cover illustrates CTD inhibition by fmk-pa, which should have cellular effects that are distinct from those of NTD inhibition by the recently reported compound BI-D1870 (see also News & Views by Frödin, p 138). Cover art by Erin Boyle, based on images and design provided by Michael Cohen.