The avalanche of easy-to-create genomics data has impacted almost all areas of medicine and science, from cancer patients and microbial diagnostics to molecular monitoring for astronauts in space. Recent technologies and algorithms from our laboratory and others demonstrate that an integrative, cross-kingdom view of patients (precision metagenomics) holds unprecedented biomedical potential to discern risk, improve diagnostic accuracy, and to map both genetic and epigenetic states around the world and in real-time. Finally, these methods and molecular tools work together to guide the most comprehensive, longitudinal, multi-omic view of human astronaut physiology in the NASA Twins Study, which lay the foundation for future long-duration spaceflight, including sequencing, quantifying, and engineering genomes in space.