The NR4A nuclear receptors, NR4A1, NR4A2 and NR4A3 are a sub-family of the nuclear receptor family of transcriptional regulators that have been linked to numerous physiological processes including metabolism, stress responses and cancer. We have previously reported that the rapid and transient induction of the NR4A family by the Melanocortin-1 Receptor (MCIR) in melanocytes plays a pivotal role in the augmentation of DNA repair by this pathway (1). Moreover, melanocytes that are homozygous for loss-of-function variants in MC1R, considered to be melanoma susceptibility genes, exhibit significantly impaired induction of the NR4A gene family. More recently, we have demonstrated a direct role for these genes in the repair of UV induced DNA lesions and observe a UV induced co-localisation of these factors with known DNA repair proteins (2). While the expression of the NR4A genes is tightly controlled in normal cells we have found constitutively high levels of expression in the majority of melanoma cell lines tested. Activating mutations in the BRAF kinase are identified in 40-50% of melanoma patients. Inhibition of the MAPK pathway using chemical inhibitors or BRAF siRNA dramatically reduces expression of the NR4A genes in melanoma cells (3). In the context of melanoma we propose that constitutive expression of NR4A proteins contributes to enhanced survival and resistance to conventional therapies of these tumours. Interestingly a recent systemic gain-of-function screen has identified both NR4A1 and NR4A2 genes as potential mediators of acquired resistance to promising new BRAF inhibitor therapies (4). Current efforts in our laboratory are aimed at identifying mechanisms by which the NR4A proteins protect melanocytic cells from genotoxic stress and contribute to melanoma tumorigenicity and resistance to therapy.