The nuclear hormone receptors, REV-ERB and REV-ERB, regulate a number of physiological functions including the circadian rhythm, lipid metabolism, and cellular differentiation. These two receptors lack the activation function-2 (AF-2) region that is associated with the ability of NHRs to recruit coactivators and activate target gene transcription. These NHRs have been characterized as constitutive repressors of transcription due to their lack of an identified ligand and their strong ability to recruit the corepressor, NCoR. Recently, the porphyrin heme was demonstrated to function as a ligand for both REV-ERBs. Heme binds directly to the ligand binding domain and regulates the ability of these NHRs to recruit NCoR to target gene promoters. This review focuses on the physiological roles that these two receptors play and the implications of heme functioning as their ligand. The prospect that these NHRs, now known to be regulated by small molecule ligands, may be targets for development of drugs for treatment of diseases associated with aberrant circadian rhythms including metabolic and psychiatric disorders as well as cancer is also addressed.