Orphan nuclear receptors are members of the nuclear receptor superfamily of ligand-activated transcription factors for which ligands and functions have not been identified. Since the cloning of the original orphans, ligands have been identified for several orphan receptors that heterodimerize with the retinoid X receptor and are no longer classified as orphan receptors. Considering the central role that nuclear receptors play in differentiation, development, metabolic regulation, homeostasis and disease, it is crucial that we understand the roles of the remaining orphans. However, the identification of ligands for those orphans that form homodimers has proven more difficult. Thus, to gain greater insight into the functions of orphan receptors, gene targeting has been used to knock out these factors and study mouse development in their absence. Here we will review the progress made in understanding the roles of the orphans GCNF and the COUP-TFs with the use of gene knockouts.