The inability to tolerate upright standing posture due to development of orthostatic hypotension is a clinical problem experienced by more than 500,000 people in the United States. In addition, orthostatic intolerance is an operational problem since as many as 25 to 64 percent of the crew members from U.S. space shuttle flights have been reported to experience presyncopal incidents during postflight stand tests. Last year alone, more than 10,000 cases of unexplained syncope were reported in active duty personnel in all U.S. military services. Many clinical investigations have focused on measurements of physiological functions in patients with orthostatic instability in an effort to identify possible mechanisms that underlie the problem. Although this approach has provided important insight into mechanisms associated with syncope, identification of causal relationships are limited by pre-existing pathologic conditions. Causal relationships can be better defined when physiological mechanisms that underlie blood pressure regulation are altered in healthy subjects by increasing or decreasing their gravity environment (so-called "G-factor" approach) and subsequent changes in orthostatic tolerance are induced. The purpose of this paper is to review data on physiological functions measured from healthy human subjects who have undergone exposure to various levels of low or high gravity in an effort to assess our understanding about mechanisms of orthostatic tolerance. Specifically, results from human subjects exposed to bedrest, spaceflight, and high sustained acceleration will be used to provide insight into the plasticity of mechanisms underlying adaptations of blood pressure regulation orthostatic performance.