Activating mutations in the MAPK pathway effectors, NRAS or BRAF, are detected in over 70% of melanomas. Accordingly, the identification of downstream targets of constitutive MAPK signalling in melanoma represents a major goal in understanding the genesis of this disease. We report here the regulation of members of the NR4A family of nuclear receptors by the BRAF-MEK-ERK cascade in melanoma cells. Expression profiling of melanoma cells in which both the NR4A1 and NR4A2 family members have been down-regulated by siRNA revealed alterations in genes associated with proliferation, survival and invasiveness of tumour cells. Notably, the up-regulation of Wnt/β-catenin pathway antagonists, DACT1 and CITED1, following NR4A1/2 ablation suggests a possible link between NR4A and β-catenin activity in melanoma cells. Taken together, these data suggest that dysregulation of NR4A nuclear receptors expression and function by the MAPK pathway may contribute to melanoma tumourigenicity.