▪Abstract Nuclear receptors modulate transcription through ligand-mediated recruitment of transcriptional coregulator proteins. The structural connection between ligand and coregulator is mediated by a molecular switch, made up of the most carboxy-terminal helix in the ligand-binding domain, helix 12. The dynamics of this switch are thought to underlie ligand specificity of nuclear receptor signaling, but the details of this control mechanism have remained elusive. This review highlights recent structural work on how the ligand controls this molecular switch and the modulation of this signaling pathway by receptor subtype and dimer partner.