We have determined the nucleotide sequence of the gene for the repressor of the pSC101 tetracycline resistance element (tetR). The repressor gene is transcribed divergently from the gene that encodes the resistance protein and encodes a putative protein of 219 amino acids. The genetic organizations of the three major types of bacterial tetracycline resistance elements thus appear to be equivalent, even though they do not show substantial nucleic acid similarity. The pSC101 repressor protein is 80% identical with the Tn 1721 repressor over its N-terminal 150 residues, whereas the C-termini of the two species are only 35% identical. Examination of the nucleic acid sequences of the regions between the two divergent promoters suggests a model in which two dimers of the tetracycline repressor molecule interact at two adjacent dyad repeats. The dimers may interact with each other, thus strengthening their grip on the operator, and affect transcription of the repressor gene. Comparison of the tetracycline (Tet) repressor with the lambda repressor suggests that the N-terminal region of the Tet repressor forms a helix-turn-helix structure and interacts with DNA in the major groove. The region of the Tet repressor implicated in DNA binding shows significant sequence similarity to a region of histone H4, suggesting that the histone may bind to DNA by means of a similar structural motif.