Enzymatic drug modification is the most common type of aminoglycoside resistance, but the molecular mechanisms involved in inducing resistance are not yet clear. A new study by Jia et al. identified a regulatory region in the leader RNA of the transcripts encoding aminoglycoside acetyl transferase and aminoglycoside adenyl transferase, which confer resistance to aminoglycoside antibiotics. They found that aminoglycosides bind to this regulatory region, mediating a conformational change that unmasks the ribosome-binding site to initiate enzyme translation. This is the first description of such a small-molecule-binding regulatory RNA, also called a riboswitch, in the context of antibiotic resistance. The aminoglycoside riboswitch is highly conserved across resistant pathogens and can be found on R plasmids responsible for multidrug resistance, thus enabling a rapid induction of resistance and even spread to other cells.