The field of environmental research has benefited greatly from the concept of biomarkers, which originally expanded our thinking by opening the “black box” between environmental exposures and manifestations of disease and dysfunction in exposed populations, as laid out in a highly influential article published in 1987 by an expert committee convened by the National Research Council. Advances in biomedical research now challenge us to revise this concept to include the microbiome as a critical stage in the progression from exposure to outcome. Incorporating the microbiome into the basic 1987 model can spur new advances and understanding in environmental health. The human microbiome as a whole comprises the majority of cells and genes of the super-organism (host and microbiome). Site-specific microbiomes are the first to encounter xenobiotics, prior to absorption across gut, skin, or respiratory system. A growing literature indicates that these microbial communities may participate in biotransformation and thus constitute a compartment to add to the original biomarker schematic. In addition, these microbiomes interact with the “niche” in which they are located and thus transduce responses to and from the host organism. Incorporating the microbiome into the environmental health paradigm will enlarge our concepts of susceptibility as well as the interactions between xenobiotics and other factors that influence the status and function of these barrier systems. This article reviews the complexities of host:microbiome responses to xenobiotics in terms of redefining toxicokinetics and susceptibility. Our challenge is to consider these multiple interactions between and within the microbiome, the immune system, and other systems of the host in terms of exposure to exogenous agents, including environmental toxicants.