In over a decade of war, numerous advancements have been made to improve overall combat-related mortality, but infectious complications remain a leading cause of both morbidity and mortality in combat-related injured personnel. Here we will attempt to compare the challenges and lessons of combat-related injuries and infections from the Vietnam War with those of OIF/OEF. Throughout the Vietnam War and OIF/OEF, there have been similar infection-related challenges faced in caring for combat-related trauma patients. Both conflicts reinforced the importance of rapid medical evacuation and definitive surgical management of war wounds. They revealed the constant evolution of infecting organisms and the challenge of increasing antimicrobial resistance. We have also seen that with decreased mortality of severely injured personnel new morbidities must be addressed. Using the foundation of fragmented research from the Vietnam War, previously successful models were assembled into joint service research institutions which have allowed these questions to be addressed. However, many questions regarding measures to reduce infectious complications in our combat-injured personnel remain unanswered. Continued research building on established knowledge is critical for continued improvements in the care of combat-related trauma patients.