Nuclear hormone receptors (NRs) function as ligand dependent DNA binding proteins that translate physiological/nutritional signals into gene regulation. Dysfunctional NR signaling leads to many disorders in reproduction, inflammation, and metabolism. The opportunity to identify novel regulatory pathways in the context of human health and disease drives the challenge to unravel the biological function of the “orphan nuclear hormone receptors”. For example, the Rev-erb (NR1D) subgroup (Rev-erbα/NR1D1 and Rev-erbβ/NR1D2) of orphan NRs are transcriptional silencers and negative regulators of ROR mediated trans-activation. The NR1D subgroup is highly enriched in peripheral tissues with onerous energy demands including skeletal muscle, brown and white adipose, brain, liver and kidney. This alludes to the involvement of this subgroup in metabolism. In this context, Rev-erbα-/- mice have a dyslipidemic phenotype. Recent studies in vascular smooth and skeletal muscle cells also suggest that the NR1D subgroup modulates inflammation by regulating IκBα/NFκB dependent gene expression. Rev-erbα has been identified as a critical regulator (and target) of circadian rhythm, a factor in blood pressure control and inflammation. Finally, two recent reports have demonstrated: (i) lithium mediated regulation of Rev-erbα stability and (ii) E75 (the Drosophila orthologue of human Rev-erbα) is tightly bound by heme, and functions as a “gas sensor” through interaction with CO/NO and interferes with the repression of DHR3 (the Drosophila orthologue of human RORα). In conclusion, the role of these receptors at the cross-roads of metabolism, inflammation, and circadian cycling underscores the importance of understanding the organ-specific function of the NR1D subgroup in homeostasis.