Human genetic variation is a determinant of nutrient efficacy and of tolerances and intolerances and has the potential to influence nutrient intake values (NIVs). Knowledge derived from the comprehensive identification of human genetic variation offers the potential to predict the physiological and pathological consequences of individual genetic differences and prevent and/or manage adverse outcomes through diet. Nutrients and genomes interact reciprocally; genomes confer differences in nutrient utilization, whereas nutrients effectively modify genome expression, stability, and viability. Understanding the interactions that occur among human genes, including all genetic variants thereof, and environmental exposures is enabling the development of genotype-specific nutritional regimens that prevent disease and promote wellness for individuals and populations throughout the life cycle. Genomic technologies may provide new criteria for establishing NIVs. The impact of a gene variant on NIVs will be dependent on its penetrance and prevalence within a population. Recent experiences indicate that few gene variants are anticipated to be sufficiently penetrant to affect average requirement (AR) values to a greater degree than environmental factors. If highly penetrant gene variants are identified that affect nutrient requirements, the prevalence of the variant in that country or region will determine the feasibility and necessity of deriving more than one AR or upper limit (UL) for affected genetic subgroups.