The field of space medicine has served the population of professional astronauts well over the many decades of human space travel, which is reflected in the considerable success of astronauts executing missions and returning to Earth in good health (rare comorbidities notwithstanding). At the same time, there are considerable gaps in our biomedical knowledge that will only scale as less fit individuals embark upon spaceflight, and we enter more extreme environments such as the Moon and Mars for longer duration missions. One means to partially fill this knowledge gap is to expand the practice of precision medicine, which we define as comprehensive genotyping and molecular phenotyping—coupled with derived countermeasures tailored to individuals and crews—to improve health and mitigate risk of disease. Improving the methods and tools of spaceflight precision medicine (PM) will improve our ability to optimize astronaut health and performance before entering space, while providing additional insight into the needs of specific astronauts while in space and upon return to Earth. A critical feature of PM in human spaceflight rests upon the foundation of complex molecular profiling, as the basis for developing these tailored countermeasures. This chapter provides an introductory overview of one means to use systems thinking to explore principles and molecular targets that are fundamental to PM in space.