Keeping crew members in good health is a major factor in the success or failure of long-duration manned space missions. Among the many possible agents that can affect the crew's general well-being, stress is certainly one of the most critical because of its implications on human health and performance, both physical and mental. Nevertheless, very few studies have been performed on this fundamental issue and none of them has addressed it in its entirety, considering its diverse physical and psychological aspects. In this work, a descriptive model is proposed to expound the mechanism and sequence of events which mediate stress. A critical analysis of the information provided by past manned spaceflights and by dedicated research performed in analogous environments is presented, and an extrapolation of the available data on human stress in such extreme conditions is proposed. Both internal and external stressors have been identified, at physical and psychosocial levels, thus providing the basis for their early detection and preventive reduction. The possible negative consequences of stress that may lead to disease in crewmembers are described. Finally, the most effective instruments which may be of help in reducing space-related human stress and treating its negative consequences are suggested.