Traumatic injury strikes unexpectedly among the healthiest members of the human population, and has been an inevitable companion of exploration throughout history. In space flight beyond the Earth's orbit, NASA considers trauma to be the highest level of concern regarding the probable incidence versus impact on mission and health. Because of limited resources, medical care will have to focus on the conditions most likely to occur, as well as those with the most significant impact on the crew and mission. Although the relative risk of disabling injuries is significantly higher than traumatic deaths on earth, either issue would have catastrophic implications during space flight. As a result this review focuses on serious life-threatening injuries during space flight as determined by a NASA consensus conference attended by experts in all aspects of injury and space flight.In addition to discussing the impact of various mission profiles on the risk of injury, this manuscript outlines all issues relevant to trauma during space flight. These include the epidemiology of trauma, the pathophysiology of injury during weightlessness, pre-hospital issues, novel technologies, the concept of a space surgeon, appropriate training for a space physician, resuscitation of injured astronauts, hemorrhage control (cavitary and external), surgery in space (open and minimally invasive), postoperative care, vascular access, interventional radiology and pharmacology.Given the risks and isolation inherent in long duration space flight, a well trained surgeon and/or surgical capability will be required onboard any exploration vessel. More specifically, a broadly-trained surgically capable emergency/critical care specialist with innate capabilities to problem-solve and improvise would be desirable. It will be the ultimate remote setting, and hopefully one in which the most advanced of our societies' technologies can be pre-positioned to safeguard precious astronaut lives. Like so many previous space-related technologies, these developments will also greatly improve terrestrial care on earth.