The environment on the International Space Station (ISS) includes a variety of potential physiologic stressors, including low gravity, elevated exposure to radiation, confined living and working quarters, a heavy workload, and high public visibility. This retrospective study examined medication use during long-duration spaceflights (>30 d). Medication records from 24 crewmembers on 20 missions longer than 30 d over a 10 yr period were examined for trends in usage rates, efficacy, and indication, as well as adverse event quality, frequency, and severity. Results were compared with those from crewmembers on shorter space shuttle missions (>16 d) and other reports of medication use by healthy adults. The most frequently used medications on the ISS were for sleep problems, pain, congestion, or allergy. Medication use during spaceflight missions was similar to that noted on the Space Shuttle and in adult ambulatory medicine, except that usage of sleep aids was about 10 times higher during spaceflight missions. There were also 2 apparent treatment failures in cases of skin rash, raising questions about the efficacy or suitability of the treatments used. Many spaceflight-related medication uses (at least 10%) were linked to extravehicular activities, exercise protocols, or equipment and operationally driven schedule changes. It seems likely that alterations in spaceflight mission operations (schedule-shifting and lighting) or hardware (extravehicular activity suits and exercise equipment) could reduce the need for a sizable fraction of medication uses.