The purpose of this paper is to review the metabolic, neurotransmitter, and morphological changes that occur in the human central nervous system (CNS) during long-duration spaceflight. If there are to be either permanent space habitats or long-duration interplanetary missions, we must determine if there will be any detrimental reversible or irreversible effects on the brain from this prolonged exposure to space. We must also determine how these effects might manifest themselves in performance, psychological, or cognitive dysfunction. The space environment has many characteristics, including microgravity, electromagnetic fields, and radiation, that may have an effect on the function and morphology of the CNS. To date, the primary focus of U.S. research has been the changes that occur in the neurovestibular system in relation to space adaptation syndrome (particularly space motion sickness). Russia, which has more experience than the U.S. with spaceflights of durations longer than several weeks, has attempted to determine the consequences of this long-duration spaceflight on the human CNS. Changes already known to occur as a result of both short- and long-duration spaceflight include alterations in the neurovestibular system, cephalic fluid shifts, loss of total body fluid, changes in electrolyte concentrations, decreases in both muscular and skeletal mass, alterations in sensory perception, changes in proprioception, and changes in human behavior. This paper will examine how these effects are related to changes in cerebral metabolism, anatomy, and neurotransmitter physiology.