Head and spinal injuries commonly occur during motor vehicle crashes (MVCs). The goal of this clinical commentary is to discuss real-life versus simulated MVCs and to present clinical, biomechanical, and epidemiological evidence of MVC-related injury mechanisms. It will also address how this knowledge may guide and inform the design of injury mitigation devices and assist in clinical decision making. Evidence indicates that there exists no universal injury tolerance applicable to the entire population of the occupants of MVCs. Injuries sustained by occupants depend on a number of factors, including occupant characteristics (age, height, weight, sex, bone mineral density, and pre-existing medical and musculoskeletal conditions), pre-MVC factors (awareness of the impending crash, occupant position, usage of and position of the seatbelt and head restraint, and vehicle specifications), and MVC-related factors (crash orientation, vehicle dynamics, type of active or passive safety systems, and occupant kinematic response). Injuries resulting from an MVC occur due to blunt impact and/or inertial loading. An S-shaped curvature of the cervical spine and associated injurious strains have been documented during rear-, frontal-, and side-impact MVCs. Data on the injury mechanism and the quantification of spinal instability guide and inform the emergent and subsequent conservative or surgical care. Such care may require determining optimal patient positioning during transport, which injuries may be treated conservatively, whether reduction should be performed, optimal patient positioning intraoperatively, and whether bracing should be worn prior to and/or following surgery. The continued improvement of traditional injury mitigation systems, such as seats, seatbelts, airbags, and head restraints, together with research of newer collision-avoidance technologies, will lead to safer motor vehicles and ultimately more effective injury management strategies.