The Human Genome Project—the complete sequencing of the chromosomal DNA of Homo sapiens—was completed in April 2003. While the acquisition of this dataset was a monumental international technical achievement and a catalyst for advancement of human molecular medicine, genetics, evolution, and much more, the regulation of how genes are activated and inhibited depends on additional immensely complex processes. Yes, a road map will lead you from point A to B, but all of the instructions to the vehicle you are driving, the rules-of-the-road that must be properly (legally) interpreted, and the environmental factors that come into play impinge on the entire process; the map shows you where to go, but nothing more. In 2008—not long after the final sequenced human chromosome was published—the five-year National Institutes of Health (NIH) Roadmap Epigenomics Program had begun, and the increasing understanding of the impact of environment on the epigenome meant that interpreting the complexity and dynamics of gene control and expression would likely be orders of magnitude more complex than simply gazing at a list of nucleotides. At about the same time as the start of the Epigenomics Program, NIH initiated the Human Microbiome Project (HMP), with the first phase being directed at identifying common elements to ‘healthy’ microbiomes in individuals lacking any overt disease. This first phase was completed in 2014, and followed by the second phase of the HMP: the integrative Human Microbiome Project (iHMP), where longitudinal studies were performed between healthy and diseased individuals in topic areas of pregnancy and preterm birth, onset of inflammatory bowel disease (IBD), and onset of Type 2 Diabetes (T2D). Just this week, several manuscripts were published in these topic areas, yielding novel insights into microbial dynamics, human host responses, and microbial inter-relationships within this array of niches. And akin to the regulation of the human genome, there is no doubt that inordinate regulatory pathways and systems-level behaviors emerge from our resident microbiomes, let alone between these microbiomes and human cells and tissues. But this is where there lies a critical opportunity in fundamental science as well: to discern new lessons of the interrelationships between eukaryotic cells and their prokaryotic partners in function, and seemingly, in evolutionary prescience. If there were any prediction to be made, it would only be grander the roles that microbiota will be shown to serve in helping humans sustain homeostasis, and that encouragement of probiotic states rather than promotion of antibiotic regimes is what connects to our signaling, chemical, and hormonal pathways. It would be fitting—should it be the humble microbiome that ratchets the controls of our own epigenetic states—dialing in gene expression in response to environmental cues or perturbations, like an ancient sidekick that has been there way longer, and knows full well how to handle the situations that those modern, fandangled eukaryotic tissues never evolved how to cope with on their own. Indeed, the embracing of the microbiome’s role in human health and disease is an essential step for the clinical sciences, but it is likely an even greater leap to unlocking what it means for us—animals and plants alike—to have become multicellular in the first place.