Consequences of the expanding commercial spaceflight industry include an increase in total number of spaceflight participants and an accompanying surge in the average number of medical comorbidities compared with government-based astronaut corps. A sequela of these developments is an anticipated rise in acute and chronic pain concerns associated with spaceflight. This review will summarize diagnostic and therapeutic areas of interest that can support the comfort of humans in spaceflight. Painful conditions that occur in space may be due to exposure to numerous stressors such as acceleration and vibration during launch, trauma associated with extravehicular activities, and morbidity resulting directly from weightlessness. Without normal gravitational forces and biomechanical stress, the hostile environment of space causes muscle atrophy, bone demineralization, joint stiffness, and spinal disc dysfunction, resulting in a myriad of pain generators. Repeated insults from abnormal environmental exposures are thought to contribute to the development of painful musculoskeletal and neuropathic conditions. As humanity invests in Lunar and Martian exploration, understanding the painful conditions that will impede crew productivity and mission outcomes is critical. Preexisting pain and new-onset acute or chronic pain resulting from spaceflight will require countermeasures and treatments to mitigate long-term health effects.