Nuclear hormone receptors are ligand-regulated transcription factors that modulate gene expression in response to small, hydrophobic hormones, such as retinoic acid and thyroid hormone. The thyroid hormone and retinoic acid receptors typically repress transcription in the absence of hormone and activate it in the presence of hormone. Transcriptional repression is mediated, in part, through the ability of these receptors to physically associate with ancillary polypeptides called corepressors. We wished to understand the mechanism by which corepressors are recruited to unliganded nuclear hormone receptors and are released on the binding of hormone. We report here that an alpha-helical domain located at the thyroid hormone receptor C terminus appears to undergo a hormone-induced conformational change required for release of corepressor and that amino acid substitutions that abrogate this conformational change can impair or prevent corepressor release. In contrast, retinoid X receptors appear neither to undergo an equivalent conformational alteration in their C termini nor to release corepressor in response to cognate hormone, consistent with the distinct transcriptional regulatory properties displayed by this class of receptors.