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The misregulation of transcription plays a key role in the development and maintenance of many human diseases. Direct regulators of transcriptional events are therefore often considered as interesting drug targets. Despite this, many such transcription factors are labelled as 'undruggable' 1 for a range of reasons grounded in the logistics of small molecule drug discovery. These factors range from intrinsic disorder at the protein level, to lack of suitable binding pockets for small molecule ligands. While such an undruggable designation is driving further innovation in medicinal chemistry, 2 it is clearly false to label all transcription factors as such. Nuclear receptors are transcription factors that are responsible for sensing molecules (such as hormones) and, in response, directly regulating the expression of specific subsets of genes. 3 By virtue of their control by small molecules, they are inherently druggable and have long been recognised as drug targets for new medicines. 1,4 There are a large number of approved drugs across many disease indications that target nuclear receptors; from ligands of the estrogen receptor (for example, Tamoxifen) for the treatment of breast cancer, to ligands of the glucocorticoid receptor (for example, Dexamethasone) for anti-inflammatory usage. Nonetheless, there are many more opportunities for the therapeutic exploitation of the nuclear receptor superfamily.REV-ERB is a member of the nuclear receptor family consisting of two similar proteins: REV-ERBα 5 and REV-ERBβ. 6 The name REV-ERB is derived from "reverse-ERB", since the NR1D1 gene that codes for REV-ERBα was mapped on the antisense DNA strand of the ERBA proto-oncogene (THRA, thyroid hormone receptor-α). 5 The closely related NR1D2 gene encodes for the other

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