Definitive management of the exsanguinating patient continues to challenge providers in multiple specialties. Significant hemorrhage may be encountered in a variety of patient care circumstances. Over the past two decades, the vast majority of data and evidence regarding transfusion in the exsanguinating patient has been based upon the trauma literature, and a large amount of recent research has investigated this subject area. In addition to the care of trauma patients, the data which have emerged can also be extrapolated to the treatment of nontrauma patients undergoing transfusion for major hemorrhage. The concept of massive transfusion is an evolving paradigm, and numerous investigations have challenged old principles while creating new controversies. The current review will examine the latest developments in the management of patients with profound hemorrhage. The challenges of dealing with the "lethal triad" will be discussed, as will the various aspects of damage control and hemostatic resuscitation. The latest literature and controversy regarding massive transfusions and massive transfusion protocols will be elucidated with inclusion of data from recent military experiences. Finally, adjuncts including the most recent advances in hemorrhage control, identification of early predictors for massive transfusion, and utilization of pharmacologic and complementary factor agent therapy will be discussed.