Broadly, nutrigenomics examines the association of exogenous nutrients and molecular responses to maintain homeostasis in an individual. Phenotypic expression profiling, often transcriptomics, has been applied to identify markers and metabolic consequences of suboptimal diet, lifestyle, or both. The decade after the Human Genome Project has been marked with advances in high-throughput analysis of biological polymers and metabolites, prompting a rapid increase in characterization of the profound nature by which our symbiotic microbiota influences human physiology. Although the technology is widely accessible to assess microbiome composition, genetic potential, and global function, nutrigenomics studies often exclude the microbial contribution to host responses to ingested nutritive molecules. Perhaps a hallmark of coevolution, milk provides a dramatic example of a diet that promotes a particular microbial community structure, because the lower infant gastrointestinal tract is often dominated by bifidobacteria that flourish on milk glycans. Systems-level approaches should continue to be applied to examine the microbial communities in the context of their host's dietary habits and metabolic status. In addition, studies of isolated microbiota species should be encouraged to inform clinical studies and interventions as well as community studies. Whereas nutrigenomics research is beginning to account for resident microbiota, the need remains to consistently consider our microscopic partners in the human holobiont.