Living organisms require a host of regulatory circuits in order to survive optimally in a given environment. Gene regulation is one of the most important mechanisms for achieving normal cellular activities and overall homeostasis. The orphan nuclear receptors (ONRs) belonging to the nuclear receptors (NR) superfamily are mediators of pleiotropic effects in multiple cell types via control of gene expression. A huge volume of studies, especially in the past two decades, has revealed the detailed structures and many functions of the ONRs. However, many biological functions governed by the ONRs through gene control remain elusive. Moreover, gene regulatory mechanisms of the ONRs are still being dissected. The ONRs can interact with other members of the NR superfamily, forming heteromeric complexes at the DNA binding sites to modulate gene transcription. Additionally, the ONRs' gene regulatory abilities are further controlled via interactions with a host of coregulators. Data from several studies have unequivocally shown that the ONRs are unique regulators of biological processes, including energy and general metabolism, immunity, growth and reproduction, cell proliferation and specialization, sensory control, and many others. Furthermore, the evidence has suggested the modulatory role played by the ONRs in the onset and progression of diseases and that targeting their activities might provide a vital tool in the treatment of various diseases. Here, the current perspective on the ONRs is being reviewed.