The striking increase in governmental and private human space flight activity with flights to suborbital, orbital, lunar, and eventually planned Mars destinations is raising the importance of clinicians’ understanding of adaptive changes that occur during space flight activities, as well as clinical risks contingent on the duration and nature of the planned activity. The purpose of this review is to provide clinicians with a framework to categorize changes and specific risks while they care for either healthy participants or individuals with preexisting pulmonary conditions engaged in space flight. This chapter will not address off-nominal operational emergency scenarios, such as fire, accidents, or accidental decompressions.