Professional space flights are becoming more ambitious. They will take astronauts farther from Earth for longer periods of time, culminating (for the foreseeable future) in missions to Mars. These missions will be qualitatively different from any that have been carried out so far. We know a great deal about how the human body (and brain) respond to space flight. Nevertheless, the history of human spaceflight tells us that one thing is to be expected: the unexpected. The historical trend tells us that as flights become longer and more challenging, new and unforeseen issues arise – medical and otherwise. This will be even more critical in those areas that we take for granted on Earth. This raises the question of how we can we provide these crews with the things that they need to thrive under extreme circumstances, so that they can carry out mission tasks and also be better representatives of humanity. Planners will have to explicitly consider the effects of the spacecraft environment, interpersonal interactions, sensory paucity, and their interactions with changing physiology, in order to maintain a high-functioning crew. This requires an integrative approach that is not yet common in aerospace.