Nucleases activated by RNA are well known, and include eukaryotic RNA-silencing complexes and prokaryotic CRISPR-Cas systems. However, this and four other recent studies report the discovery of an RNA-activated protease {1-4}. In certain CRISPR-Cas systems called type III-E, a caspase-like protease has previously been found to associate with the CRISPR-Cas effector complex {5}. The CRISPR-Cas effector uses genomically encoded RNA to recognize and degrade complementary nucleic acids, and thereby confers immunity against viruses and other parasitic genetic elements. All five studies now show that binding of complementary RNA also activates the associated protease. Curiously, only imperfect complementarity activates the protease, perhaps to avoid activation by self RNA. The reason behind this conundrum is revealed by cryo-electron microscopy (cryo-EM) structures of the complex in different RNA-bound states. In the absence of complementary RNA, or when the complementarity is perfect, two key proteolytic residues are kept separated from each other. Imperfect complementarity displaces a regulatory helix, which then pulls the residues closer together. The consequences of activating the protease are unclear, but likely trigger additional immune responses. The studies show that the activated protease cleaves an endogenous bacterial protein, whose cleavage products may be cytotoxic and thus prevent infections from spreading to neighboring cells. This substrate protein also binds a transcription factor, which may be released upon cleavage to induce expression of alternative defense genes. Interestingly, the protease has recently been implicated in the proteolytic activation of bacterial gasdermins {6}, but whether this function is similarly triggered by foreign RNA remains to be explored. Activation of the protease by specific nucleic acids may have innovative biotechnological applications, for example in programmable RNA sensing.