Nutritional genomics offers a way to optimize human health and the quality of life. It is an attractive endeavor, but one with substantial challenges. It encompasses almost all known aspects of science, ranging from the genomes of humans, plants, and microorganisms, to the highest levels of food science, analytical science, computing, and statistics of large systems, as well as human behavior. This paper describes the underlying biochemistry that is targeted by the principal issues in nutritional genomics, which entails genomics, transcriptomics, proteomics, and metabolomics. A major feature relevant to nutritional genomics is the single nucleotide polymorphisms in genes that interact with nutrients and other bioactive food components. These genetic changes may lead to alterations in absorption, metabolism, and functional responses to bioactive nutritional factors. Bioactive food components may also regulate gene expression at the transcriptome, protein abundance, and/or protein turnover levels. Even if all of these variables are known, additional variables to be considered include the nutritional variability of the food (unprocessed and processed), the amount that is actually eaten, and the eating-related behaviors of those consuming the food. These challenges are explored within the context of soy intake. Finally, the importance of international cooperation in nutritional genomics research is presented.