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The subsequent initiative to sequence our bodies’ “second genome,” represented by the NIH-funded Human Microbiome Project and its European equivalent, Meta-HIT, has catalyzed numerous discoveries and sparked interest in identifying the contributions of our microbiota to our health, development, behavior, and emotions (summarized in Table 1 of reference 4). Foremost among these paradigm shifts has been the realization that our species, Homo sapiens, is at least as microbial as human in terms of cell numbers ( 2) and much more so in terms of genetic potential ( 3).

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Massively parallel DNA sequencing platforms plus significant technological advances derived from this previous international, public, and private initiative continue to drive economic development and numerous paradigm shifts across domains of the biological, physical, and social sciences. Now well into the 21st century, the Human Genome Project fades from our rearview mirror but its lasting impact extends far into our future ( 1). These efforts will improve prediction of ecosystem response and enable the development of new, responsible, microbiome-based solutions to significant challenges of our time. From the parallelization of gene function testing to precision manipulation of genes, communities, and model ecosystems and development of novel analytical and simulation approaches, we outline strategies to move microbiome research into an era of causality. Given the extensive influence of microorganisms across our biosphere, we propose that a coordinated, cross-disciplinary effort is required to understand, predict, and harness microbiome function. The challenges we face to supply food, energy, and clean water while maintaining and improving the health of our population and ecosystems are significant. Humankind has had a profound influence on the biosphere, manifested as global climate and land use changes, and extensive urbanization in response to a growing population. Microorganisms have shaped our planet and its inhabitants for over 3.5 billion years.

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