Mycobacterium tuberculosis EthR is a repressor of ethA, a gene encoding a mono-oxygenase required for the activation of the prodrug ethionamide. Two EthR crystal structures have been reported recently, either in a ligand-bound (Frenois F, Engohang-Ndong J, Locht C, Baulard AR, Villeret V. Mol Cell 2004; 16: 301-7) or in a presumed apo conformation (Dover LG, Corsino PE, Daniels IR, Cocklin SL, Tatituri V, Besra GS, Futterer K. J Mol Biol 2004; 340: 1095-105). In order to infer the EthR induction mechanism, we have compared these structures. It appears that the two structures are in a conformation incompatible with repressor function, due to the presence in both proteins of fortuitous and structurally unrelated ligands. This observation paves the way to the design of specific drugs that could increase the sensitivity of M. tuberculosis to ethionamide.