Hemorrhagic shock is a leading cause of death in trauma patients worldwide. Bleeding control, maintenance of tissue oxygenation with fluid resuscitation, coagulation support, and maintenance of normothermia remain mainstays of therapy for patients with hemorrhagic shock. Although now widely practised as standard in the USA and Europe, shock resuscitation strategies involving blood replacement and fluid volume loading to regain tissue perfusion and oxygenation vary between trauma centers; the primary cause of this is the scarcity of published evidence and lack of randomized controlled clinical trials. Despite enormous efforts to improve outcomes after severe hemorrhage, novel strategies based on experimental data have not resulted in profound changes in treatment philosophy. Recent clinical and experimental studies indicated the important influences of sex and genetics on pathophysiological mechanisms after hemorrhage. Those findings might provide one explanation why several promising experimental approaches have failed in the clinical arena. In this respect, more clinically relevant animal models should be used to investigate pathophysiology and novel treatment approaches. This review points out new therapeutic strategies, namely immunomodulation, cardiovascular maintenance, small volume resuscitation, and so on, that have been introduced in clinics or are in the process of being transferred from bench to bedside. Control of hemorrhage in the earliest phases of care, recognition and monitoring of individual risk factors, and therapeutic modulation of the inflammatory immune response will probably constitute the next generation of therapy in hemorrhagic shock. Further randomized controlled multicenter clinical trials are needed that utilize standardized criteria for enrolling patients, but existing ethical requirements must be maintained. © 2008 BioMed Central Ltd.