Nuclear receptor heterodimers recognize response elements composed of two direct repeats of the consensus sequence 5′-AGGTCA-3′ separated by one to five base pairs. The 1.9 Å crystal structure of the complex formed by the DNA-binding domains of the 9-cis retinoic acid receptor and thyroid hormone receptor bound to a thyroid-response element shows that the subunits interact through a DNA-supported interface involving the carboxy-terminal extension of the DNA-binding domain of the thyroid hormone receptor. The stereochemistry suggests a mechanism by which heterodimers recognize the inter-half-site spacing between direct repeats.