ESA Medical Operations has a long experience in collaborating with the US American and Russian space-flight programs since the early 1980’s with more than 40 supported space missions. As one of five International Partners, ESA is involved in the construction and operation of the International Space Station. Multilateral Memoranda of Understanding define the policies and rules of this major international endeavor. The medical support and health care of humans, living, working and researching in space, is the most important element of space flight operations. ESA is acknowledging its responsibility to preserve health and well being of its astronauts by implementing a robust medical support infrastructure, however, not neglecting the fact that this needs to be done on the basis of a multinational partnership. The US and Russian medical support programs have a long tradition. ESA does not have its own transportation access to space and therefore heavily depends on the two nations, offering launch services. ESA’s approach to define and implement a medical support concept was not to decide on one or the other or to just follow a program according to political boundaries. To the contrary, ESA Medical Operations realized that the ISS program opens the door for creative solutions, to combine established and proven concepts, to benefit from the experience of both big Partners. And even though ESA is a small Partner, we used the opportunities to propose new approaches, to critically analyze the current concepts, and to even question established processes. Our geographical location and our cultural background, combined with the experience gained in both space-flight programs enabled us to proactively facilitate such processes. Moreover, ESA by itself working in an environment of many nationalities, cultures and languages helped in positioning ourselves, to increase our reputation among the Partners and to promote a multicultural approach to space-medicine. By understanding our heritage it becomes evident that besides all attempts to harmonize and standardize medical care, preserving the cultural diversity and identity and respecting skills and experiences provided by all Partners is essential to operate the Space Station in a truly global and international fashion. With the delivery of the ESA elements – the scientific laboratory “COLUMBUS” and the Automated Cargo Vehicle “ATV”, ESA became a full member of the ISS program. This allows the Agency to have in average one ESA astronaut per year supporting a mission of about 180 days. The current mission in fact marks the 5th long-duration ISS spaceflight with ESA astronaut participation. But a majority of their time, astronauts are living and working on this planet under normal gravity conditions. Maintaining the physical and mental health and fitness as an important element of space-medicine healthcare with the goal to “protect” this precious human asset. Therefore a continuous preventive medical program and intensive post-mission rehabilitation exercises follow careful medical selection. As medical support is not “just waiting for the patient to see the doctor”, a robust ground infrastructure and ground support team needed to be defined and implemented. Furthermore, space-medicine is not only “the doctors”; it is a carefully orchestrated team effort by many professions, enabling at the end the physician to make a clinical decision. This presentation will provide an overview of the main elements of the ESA medical operations support program and its implementation within ESA and in coordination with the other Partners. By using live examples of the current and recent mission activities, an overview of the complexity, the problems encountered, the opportunities for the future, and possible impacts on terrestrial medical applications will be presented.