Urate is the end product of purine metabolism in humans. Humans and higher primates have much higher serum urate levels than other species because they lack the enzyme uricase, which converts urate into its break-down product allantoin. Serum urate levels are highly heritable, suggesting a strong genetic component. Reduced excretion of urate by the kidney is the main cause for elevated urate levels which can lead to gout. Renal urate transport is complex and still poorly understood; although multiple renal urate transporters have been characterized in model systems, their role in human disease is mostly unclear. Genome-wide association studies (GWAS) have successfully identified common single nucleotide polymorphisms (SNPs) associated with a wide variety of complex diseases, but cannot address gene function nor establish causality of disease-associated SNPs. We recently used GWAS to identify SNPs in a genomic region on chromosome 4 that associate with serum urate levels and gout, a consequence of elevated urate levels. Here we show using functional assays that human ATP-binding cassette, sub-family G, 2 (ABCG2), encoded by the ABCG2 gene contained in this region, is a hitherto unknown urate efflux transporter. We further show that native ABCG2 is located in the brush border membrane of kidney proximal tubule cells, where it mediates renal urate secretion. Introduction of the mutation Q141K encoded by the common SNP rs2231142 by site-directed mutagenesis resulted in 53% reduced urate transport rates compared to wildtype ABCG2 (p<0.001). Data from a population-based study of 14,783 individuals support rs2231142 as the causal variant in the region and show highly significant associations with urate levels and gout. Our data indicate that at least 10% of all gout cases in whites are attributable to this causal variant. With around 6 million US individuals suffering from often insufficiently treated gout, ABCG2 represents an attractive new drug target.