Exposure to ionizing radiation may negatively impact skeletal integrity during extended spaceflight missions to the moon, Mars, or near-Earth asteroids. However, our understanding of the effects of radiation on bone is limited when compared to the effects of weightlessness. In addition to microgravity, astronauts will be exposed to space radiation from solar and cosmic sources. Historically, radiation exposure has been shown to damage both osteoblast precursors and local vasculature within the irradiated volume. The resulting suppression of bone formation and a general state of low bone-turnover is thought to be the primary contributor to bone loss and eventual fracture. Recent investigations using mouse models have identified a rapid, but transient, increase in osteoclast activity immediately after irradiation with both spaceflight and clinically-relevant radiation qualities and doses. Together with a chronic suppression of bone formation after radiation exposure, this acute skeletal damage may contribute to long-term deterioration of bone quality, potentially increasing fracture risk. Direct evidence for the damaging effects of radiation on human bone are primarily demonstrated by the increased incidence of fractures at sites that absorb high doses of radiation during cancer therapy: exposures are considerably higher than what could be expected during spaceflight. However, both the rapidity of bone damage and the chronic nature of the changes appear similar between exposure scenarios. This review will outline our current knowledge of space and clinical exploration exposure to ionizing radiation on skeletal health.