Sequence polymorphisms linked to human diseases and phenotypes in genome-wide association studies often affect noncoding regions. A SNP within an intron of the gene encoding Interferon Regulatory Factor 4 (IRF4), a transcription factor with no known role in melanocyte biology, is strongly associated with sensitivity of skin to sun exposure, freckles, blue eyes, and brown hair color. Here, we demonstrate that this SNP lies within an enhancer of IRF4 transcription in melanocytes. The allele associated with this pigmentation phenotype impairs binding of the TFAP2A transcription factor that, together with the melanocyte master regulator MITF, regulates activity of the enhancer. Assays in zebrafish and mice reveal that IRF4 cooperates with MITF to activate expression of Tyrosinase (TYR), an essential enzyme in melanin synthesis. Our findings provide a clear example of a noncoding polymorphism that affects a phenotype by modulating a developmental gene regulatory network. Display omitted •Sequence variation in IRF4 is associated with pigmentation features including freckles•This sequence is located in an enhancer element that affects expression of IRF4•The transcription factors MITF and TFAP2A regulate expression from this element•Together, MITF and IRF4 affect regulation of the pigmentation enzyme TYR A polymorphism in a noncoding region of IRF4, a transcription factor involved in immune signaling, is found to affect human pigmentation. This polymorphism affects the ability of the transcription factors TFAP2A and MITF to regulate IRF4 levels, which in turn results in reduced levels of the pigmentation enzyme Tyrosinase.