Of the large nuclear hormone receptor superfamily of proteins, orphan nuclear receptors have remained a mystery owing to their lack of identified ligands and their constitutive nature. Now, structures of several ligand-binding domains of orphan receptors have provided some surprising insights that were not anticipated from molecular studies. Therefore, most orphan nuclear receptors have now been ‘adopted’ and their regulation has been shown to range from true ligand-independence to highly promiscuous ligand-dependence. Former orphan receptors have been found to contain ligand-binding pockets that range in volume from vast (>1600ų) to non-existent and have been shown to generate surface AF2 motifs that range from being multifunctionally active to distinctly inactive. Insights from these new structures illustrate how powerful a structural biology approach can be when integrated with molecular and cellular physiology.