Background: Uncontrolled bleeding continues to be a major cause of mortality in trauma, cardiac surgery, postpartum hemorrhage and liver failure. The aim of this paper is to assess the evidence supporting the efficacy of activated recombinant factor VII (rFVIIa) administration in these settings. Methods: Electronic literature search. Results: Numerous retrospective trials have mostly shown a decrease in blood transfusion requirements with no increase in thromboembolic events (TEE), but major limitations in trial design make generalization difficult. In most retrospective reports rFVIIa has been administered as a last-ditch attempt to control bleeding, when acidosis, hypothermia and coagulation factor depletion may not allow optimal rFVIIa effect. Prospective randomized controlled trials have not shown any effect of rFVIIa on mortality or TEE, although some have shown a reduction in RBC requirement. Conclusion: Stipulated transfusion protocols in prospective trials have reduced anticipated mortality among controls and make future trials for mortality effect unlikely in view of large sample size requirements. Establishment of these protocols and rapid hemostasis are likely to have greater benefits than administration of a single agent.