Experiments on human spatial orientation were conducted on four crewmembers of Space Shuttle Spacelab Mission 1. This introductory paper presents the conceptual background of the project, the relationship among the experiments and their relevance to a "sensory reinterpretation hypothesis". Detailed experiment procedures and results are presented in the accompanying papers in this series. The overall findings are discussed in this article as they pertain to the following aspects of hypothesized sensory reinterpretation in weightlessness: utricular otolith afferent signals are reinterpreted as indicating head translation rather than tilt, sensitivity of reflex responses to footward acceleration is reduced, and increased weighting is given to visual and tactile cues in orientation perception and posture control. Three subjects developed space motion sickness symptoms, which abated after several days. Head movements, as well as visual and tactile cues to orientation influenced symptoms in a manner consistent with the sensory-motor conflict theory of space motion sickness. Six short duration tests of motion sickness susceptibility, conducted pre-flight, failed to predict sickness intensity in weightlessness. An early otolith-spinal reflex, measured by electromyography from the gastrocnemius-soleus muscles during sudden footward acceleration, was inhibited immediately upon entering weightlessness and declined further during the flight, but was unchanged from pre-flight when measured shortly after return to earth. Dynamic visual-vestibular interaction was studied by measuring subjective roll self-motion created by looking into a spinning drum. Results suggest increased weighting of visual cues and reduced weighting of graviceptor signals in weightlessness. Following the 10 day flight, erect posture with eyes closed was disturbed for several days.(ABSTRACT TRUNCATED AT 250 WORDS)