In the 1990s, Canada, member states of the European Space Agency, Japan, the Russian Federation, and the United States entered into an international agreement Concerning Cooperation on the Civil International Space Station. Among the many unique infrastructure challenges, partners were to develop a comprehensive international medical system and related processes to enable crew medical certification and medical support for all phases of missions, in a framework to support a multilateral space program of unprecedented size, scope, and degree of integration. During the Shuttle/Mir Program, physicians and specialized experts from the United States and Russia studied prototype systems and developed and operated collaborative mechanisms. The 1998 NASA Memoranda of Understanding with each of the other four partners established the Multilateral Medial Policy Board, the Multilateral Space Medicine Board, and the Multilateral Medical Operations Panel as medical authority bodies to ensure International Space Station (ISS) crew health and performance. Since 1998, the medical system of the ISS Program has ensured health and excellent performance of the international crewsan essential prerequisite for the construction and operation of the ISSand prevented mission-impacting medical events and adverse health outcomes. As the ISS is completing its second decade of crewed operation, it is prudent to appraise its established medical framework for its utility moving forward in new space exploration initiatives. Not only the ISS Program participants, but other nations and space agencies as well, concomitant with commercial endeavors in human spaceflight, can benefit from this evidence for future human exploration programs.