Injury impacts all aspects of physiology; more so with increasing severity. Survival from massive injury depends upon the ability to compensate for massive physiological derangements. Very often, injured patients are young and healthy; however, the demographics of injured patients arriving at the hospital are changing, as populations age and trauma systems develop. Preexisting medical comorbidities can limit or alter the physiological response to injury. This chapter looks at what is currently known about the impact of preexisting medical conditions during all phases of injury and highlights areas of current research to try and improve outcomes in this increasingly recognized subset of injured patients.