Nuclear receptors form the largest known family of transcription factors and have a crucial role in nearly all aspects of vertebrate development and adult physiology by transducing the effects of hormones into transcriptional responses. Members of the steroid/thyroid hormone nuclear receptor (NR) superfamily bind specific DNA elements and function as ligand activated transcription factors. This group includes the `orphan receptors′ which have no known ligands in the `classical sense′ and appear to be the ancient progenitors of this receptor superfamily. The Rev-erb family of proteins are orphan members of the receptor superfamily. Two isoforms of the Rev-erb family have been isolated from mammalian genotypes, Rev-erbA[alpha] and Rev-erbA[beta]/RVR. Major differences between the two isoforms occur within the hyper-variable A/B and D regions of the proteins. Both isoforms are expressed in a wide range of tissues and are present in all major organs. Rev-erbA[alpha] mRNA is upregulated during adipocyte differentiation but repressed during myogenesis. These orphan receptors are closely related to the ROR/RZR[alpha] gene family (retinoic acid receptor related orphan receptor) and the Drosophila orphan receptor, E75A, particularly in the DNA-binding domain (DBD) and the putative ligand-binding domain (LBD). RVR and Rev-erbA[alpha] bind as monomers to an asymmetric ( A / T ) 6 RGGTCA motif. The Rev-erb family has also been demonstrated to bind as homodimers to novel HREs consisting of two tandemly arranged AGGTCA motifs, separated by 2 bp with unique 5′ flanking and spacer nucleotides (RevDR-2). Reports on the transcriptional properties of the Rev-erb family were initially conflicting. Rev-erbA[alpha] was first reported to act as a constitutive activator of transcription through its cognate monomeric asymmetric motif. Recently, it has been demonstrated that members of the Rev-erb family are, in fact, dominant repressors of transcription. Rev-erbA[beta] is expressed in the central nervous system, skeletal and dorsal muscles, spleen and mandibular and maxillar processes. During embryogenesis RVR is expressed in the notochord and neural tube, but its function/role during differentiation and mammalian development remains obscure.