Among the numerous steroidal and orphan nuclear receptors encoded within mammalian genomes, several are involved in the regulation of apoptosis. The authors review here recent studies on members of the Nur77 family of orphan receptors including Nur77, Nurr1 and Nor-1. These transcription factors were initially identified in nerve cells, but also play key roles in the development and the effector functions of T lymphocytes and other cells and tissues. Nur77 can also act as a modulator of transcription for other orphan steroid receptors. Regulation of the Nur77 orphan receptor family members are tightly associated with transcriptional co-factors including co-repressors and co-activators. Also, one interesting aspect of the Nur77 orphan receptor family members is that depending on its location in the mitochondria or nucleus, these orphan receptors exhibit differential roles in determining cell death or cell growth. Numerous studies demonstrated the importance of Nur77 subfamily members in regulations of early embryogenesis, thymocyte negative selection, gene expression in hypothalamic-pituitary adrenal axis, chronic inflammatory response, and vascular smooth muscle cell proliferation. This review intends to integrate the importance of nuclear receptors in health and disease, and as potential targets for drug discovery by comparing the difference and similarity in the biochemical mechanisms of action used by the classic steroid/endocrine receptors and the orphan receptors to lead to identification of novel targets in manipulating the transcriptional functions and physiologic pathways for the orphan nuclear receptors.