Nutrigenomics refers to the interaction between one’s diet and his/her genes. These interactions can markedly influence digestion, absorption, and the elimination of bioactive food components, as well as influence their site of actions/molecular targets. Nutrigenomics comprises nutrigenetics, epigenetics, and transcriptomics, coupled with other “omic,” such as proteomics and metabolomics, that apparently account for the wide variability in cancer risk among individuals with similar dietary habits. Multiple food components including essential nutrients, phytochemical, zoochemicals, fungochemical, and bacterochemicals have been implicated in cancer risk and tumor behavior, admittedly with mixed results. Such findings suggest that not all individuals respond identically to a diet. This chapter highlights the influence of single-nucleotide polymorphism, copy number, epigenetic events, and transcriptomic homeostasis as factors influencing the response to food components and ultimately health, including cancer risk. Both breast and colorectal cancers are reviewed as examples about how nutrigenomics may influence the response to dietary intakes. As the concept that “one size fits all” comes to an end and personalized approaches surface, additional research data will be required to identify those who will benefit most from dietary change and any who might be placed at risk because of an adjustment.