From clinical and laboratory studies of specific coagulation defects induced by injury, damage control resuscitation (DCR) emerged as the most effective management strategy for hemorrhagic shock. DCR of the trauma patient who has sustained massive blood loss consists of 1) hemorrhage control; 2) permissive hypotension; and 3) the prevention and correction of trauma-induced coagulopathies, referred to collectively here as acute coagulopathy of trauma (ACOT). Trauma patients with ACOT have higher transfusion requirements, may eventually require massive transfusion, and are at higher risk of exsanguinating. Distinct impairments in the hemostatic system associated with trauma include acquired quantitative and qualitative platelet defects, hypocoagulable and hypercoagulable states, and dysregulation of the fibrinolytic system giving rise to hyperfibrinolysis or a phenomenon referred to as fibrinolytic shutdown. Furthermore, ACOT is a component of a systemic host defense dysregulation syndrome that bears several phenotypic features comparable with other acute systemic physiological insults such as sepsis, myocardial infarction, and postcardiac arrest syndrome. Progress in the science of resuscitation has been continuing at an accelerated rate, and clinicians who manage catastrophic blood loss may be incompletely informed of important advances that pertain to DCR. Therefore, we review recent findings that further characterize the pathophysiology of ACOT and describe the application of this new information to optimization of resuscitation strategies for the patient in hemorrhagic shock.