The most common prokaryotic signal transduction mechanisms are the one-component systems in which a single polypeptide contains both a sensory domain and a DNA-binding domain. Among the >20 classes of one-component systems, the TetR family of regulators (TFRs) are widely associated with antibiotic resistance and the regulation of genes encoding small-molecule exporters. However, TFRs play a much broader role, controlling genes involved in metabolism, antibiotic production, quorum sensing, and many other aspects of prokaryotic physiology. There are several well-established model systems for understanding these important proteins, and structural studies have begun to unveil the mechanisms by which they bind DNA and recognize small-molecule ligands. The sequences for more than 200,000 TFRs are available in the public databases, and genomics studies are identifying their target genes. Three-dimensional structures have been solved for close to 200 TFRs. Comparison of these structures reveals a common overall architecture of nine conserved α helices. The most important open question concerning TFR biology is the nature and diversity of their ligands and how these relate to the biochemical processes under their control.