The transcriptional regulators of the TetR family act as chemical sensors to monitor the cellular environment in many bacterial species. To perform this function, members of the TetR family harbor a diverse ligand-binding domain capable of recognizing the same series of compounds as the transporters they regulate. Many of the regulators can be induced by a wide array of structurally unrelated compounds. Binding of these structurally unrelated ligands to the regulator results in a conformational change that is transmitted to the DNA-binding region, causing the repressor to lose its DNA-binding capacity and allowing for the initiation of transcription. The multi-drug binding proteins AcrR of Escherichia coli and CmeR from Campylobacter jejuni are members of the TetR family of transcriptional repressors that regulate the expression of the multidrug resistant efflux pumps AcrAB and CmeABC, respectively. To gain insights into the mechanisms of transcriptional regulation and how multiple ligands induce the same physiological response, we determined the crystal structures of the AcrR and CmeR regulatory proteins. In this review, we will summarize the new findings with AcrR and CmeR, and discuss the novel features of these two proteins in comparison with other regulators in the TetR family.