Stress is a word that is used throughout the world, and it has many meanings. Physiologically, cortisol and adrenalin are stress hormones and their response is usually the focus of disucssions of stress. However, there are multiple biological mediators besides the adrenal stress hormones that are responsible for adaptation in situations that induce a response and help us stay alive. The brain is the central organ of stress and adaptation because it determines not only what is threatening but also determines the physiological and behavioral responses. The study of healthy humans experiencing high levels of stress in confinement and isolation, and in other space analogous environments, allows us to draw clear causal links between stress and physiological disequilibrium and disease. Understanding the interaction between stress, and the human body and mind will lead to better healthcare not only for astronauts, but also for the vast majority of us who will never escape gravity’s pull.