BACKGROUND: Blood operations are constrained by many limitations in combat settings. As a result there are many challenges that require innovative solutions. STUDY DESIGN AND METHODS: This is a descriptive overview of blood product usage and transfusion medicine adaptations that have been employed by the US military to support combat operations in Iraq and Afghanistan between November 2001 and December 2010. RESULTS: Transfusion medicine challenges have included the need for rapid transport of large quantities of blood products from the United States to Iraq and Afghanistan, risks and appropriate countermeasures associated with blood products collected in the theater of operations, availability of fresh-frozen plasma at forward surgical facilities, need for platelets (PLTs) in combat, and the need to support constant and evolving changes in transfusion and resuscitation protocols. A decrease in the storage age of red blood cells (RBCs) transfused to combat casualties has been achieved. There has been an increase in the ratio of plasma and PLTs to RBCs transfused, increased availability of plasma and apheresis PLTs to facilitate this approach, and a continuous effort to improve the safety of using fresh whole blood and apheresis PLTs collected in combat. A number of clinical practice guidelines are in place to address these processes. CONCLUSION: This multidisciplinary approach has successfully addressed many complicated and challenging issues regarding blood operations and transfusion practices for combat casualties.