In the transition from the short-duration missions of the Space Shuttle era to long-duration exploration missions, the health and safety of crewmembers must be ensured. The body undergoes many complex physiological changes as a result of its adaptation to a microgravity environment and U.S. and Soviet experiences have shown that time is required for readaptation to gravity. The consequences of these changes for the extended exploration missions envisioned for the future are unknown. A Mars mission may require crewmembers to spend many months in microgravity, and then work effectively in a one-third gravity environment. Other problems may arise when returning crewmembers must readapt to Earth's gravity. Life Sciences activities are being planned to systematically address the physiological issues involved with long-term manned exploration missions, through ground-based studies and flight investigations on the Shuttle and Space Station Freedom. The areas of focus are artificial gravity, radiation, health care, and space human factors.