The American and Russian/Soviet space programs independently uncovered psychosocial risks inherent in long-duration space missions. Now that these two countries are working together on the International Space Station (ISS), American-Russian cultural differences pose an additional set of risk factors. These may echo cultural differences that have been observed in the general population of the two countries and in space analogue settings, but little is known about how relevant these are to the select population of space program personnel. The evidence for the existence of mission-relevant cultural differences is reviewed and includes cultural values, emotional expressivity, personal space norms, and personality characteristics. The review is focused primarily on Russia and the United States, but also includes other ISS partner countries. Cultural differences among space program personnel may have a wide range of effects. Moreover, culture-related strains may increase the probability of distress and impairment. Such factors could affect the individual and interpersonal functioning of both crewmembers and mission control personnel, whose performance is also critical for mission safety and success. Examples from the anecdotal and empirical literature are given to illustrate these points. The use of existing assessment strategies runs the risk of overlooking important early warning signs of behavioral health difficulties. By paying more attention to cultural differences and how they might be manifested, we are more likely to detect problems early while they are still mild and resolvable.