As we approach the end of the first 50 years of human space travel, much has been learned about adaptation to microgravity and the risks associated with extended-duration space exploration. As the frequency and duration of flights grew, nutrition issues became more critical and the questions to be answered became more complex: What are the nutrient requirements for space travelers? Can nutrients be used as tools to mitigate the negative effects of space travel on humans? How does nutrition interrelate with other physiological systems (such as muscle, bone, and cardiovascular system) and their adaptation to microgravity? Much research has been done over the decades in both actual spaceflight and ground-based analogs. We review here much of what is known, and highlight areas of ongoing research and concerns for future exploration of the Moon, Mars, and beyond.