The ability to link dietary consumption of prebiotic food ingredients and probiotic microorganisms to health benefits rests, in part, on our ability to identify both the extent to which these factors alter human microbiome activity and/or structure and the ability to engage eukaryotic cells necessary to transduce signals originating from the microbiome. The human microbiome consists of bacterial, archaeal, and fungal components that reside in mucosal surfaces of the gut, the airways, and the urogenital tract. Characterization of the symbiotic nature of the relationship between eukaryotic cells and the bacterial and archaeal components of the microbiota has revealed significant contributions in energy balance, bowel function, immunologic function, sensory perception, glycemic control, and blood pressure regulation. Elucidating the complex interactions between the microbiota and their associated epithelial, immune, and neural cells may provide mechanistic insights and a rational basis for our belief that dietary consumption of probiotic microorganisms and prebiotics produces health benefits.