Human sweet taste perception is mediated by the heterodimeric G-protein coupled receptor complex encoded by the TAS1R2 and TAS1R3 genes [1-7]. The extent of variation in these genes has been recently characterized , but the functional consequences of such variation are unknown. In this study we report that two C/T single nucleotide polymorphisms located at positions −1572 (rs307355) and −1266 (rs35744813) upstream of the TAS1R3 coding sequence strongly correlate with human taste sensitivity to sucrose, and explain 16% of population variability in perception. Individuals who carry T alleles display reduced sensitivity to sucrose compared to those who carry C alleles at these nucleotide positions. Using a luciferase reporter assay, we demonstrate that the T allele of each SNP results in reduced promoter activity in comparison to the C alleles, consistent with the phenotype observed in humans. We also found that the TAS1R3 promoter region extending from position −1700 to −1000 harbors a novel composite cis-acting element that has a strong silencing effect on promoter activity. We conclude that the rs307355 and rs35744813 SNPs affect gene transcription by altering the function of this regulatory element. A worldwide population survey reveals that the T alleles of rs307355 and rs35744813 occur at lowest frequencies in European populations. We propose that inherited differences in TAS1R3 transcription account for a substantial fraction of worldwide differences in human sweet taste perception.