A single nucleotide polymorphism in the promoter of the multifunctional cytokine Interleukin 4 (IL4) affects the binding of NFAT, a key transcriptional activator of IL4 in T cells. This regulatory polymorphism influences the balance of cytokine signaling in the immune system, with important consequences-positive and negative-for human health. We determined that the NFAT binding site is unique to humans; it arose by point mutation along the lineage separating humans from other great apes. We show that its frequency distribution among human subpopulations has been shaped by the balance of selective forces on IL4's diverse roles. New statistical approaches, based on parametric and nonparametric comparisons to neutral variants typed in the same individuals, indicate that differentiation among subpopulations at the IL4 promoter polymorphism is too great to be attributed to neutral drift. The allele frequencies of this binding site represent local adaptation to diverse pathogenic challenges; disease states associated with the common derived allele are side-effects of positive selection on other IL4 functions.