Recent GWAS evidence has revealed the presence of a SNP within the fouth intron of the Interferon Regulatory Factor 4 gene (IRF4), which is associated with pigmentation, nevus formation, UV sensitivity and melanoma suceptibility 1 . The rs12203592_T SNP, which is associated with a lighter pigmentation phenotype, is only found in around 16% of Caucasian populations, whilst the C allele variant is homozygous in Chinese, Japanese and African populations. While this association has been identified in a number of independent GWAS the functional effect of the SNP and role of IRF4 in melanocyte cell function is unknown. IRF4 and other members of the IRF family have been recognised as key mediators of differentiation and cellular function in other systems and are crucial regulators of interferon responses in these biological contexts. Interestingly, an interferon (IFN)-gamma-dependent crosstalk between melanocytes and macrophages has recently been reported that allows UVB-irradiated melanocytes to evade immunosurveillance, which ultimately contributes to melanomagenesis 2 . Using primary human melanocytes, we have demonstrated differential expression of IRF4 between individuals homozygous for the T and C allele, with C/C individuals having significantly higher IRF4 expression. Analysis of the cis-regulatory activity of the IRF4 intron 4 suggests the SNP directly effects the transcriptional regulation of the IRF4 gene. To gain further insight into the function of IRF4 in melanocytes, transcriptome profiling of primary human melanocytes following siRNA-mediated IRF4 knock-down was performed, in the presence or absence of IFN-gamma. Validation of selected candidate genes in melanocytes of known IRF4 genotype provides strong evidence for a role for IRF4 in mediating melanocytic interferon responses. Current investigations are aimed at further understanding the role of IRF4 in human pigmentation and exploring the link between differential IRF4 expression and the response of melanocytes to IFNɣ signalling.