Nuclear hormone receptors are ligand-regulated transcription factors that play critical roles in metazoan homeostasis, development, and reproduction. Many nuclear hormone receptors exhibit bimodal transcriptional properties and can either repress or activate the expression of a given target gene. Repression appears to require a physical interaction between a receptor and a corepressor complex containing the SMRT/TRAC or N-CoR/RIP13 polypeptides. We wished to better elucidate the rules governing the association of receptors with corepressors. We report here that different receptors interact with different domains in the SMRT and N-CoR corepressors and that these divergent interactions may therefore contribute to distinct repression phenotypes. Intriguingly, different isoforms of a single nuclear hormone receptor class also differ markedly in their interactions with corepressors, indicative of their nonidentical actions in cellular regulation. Finally, we present evidence that combinatorial interactions between different receptors can, through the formation of heterodimeric receptors, result in novel receptor-corepressor interactions not observed for homomeric receptors.