Cell-free hemoglobin-based blood substitutes (HBBSs)—infusible, oxygen-carrying liquids with a long shelf life and no need for refrigeration or cross-matching—could be lifesaving for patients with hemorrhagic shock who are treated in remote settings. However, some clinical trials of HBBSs have raised questions about their safety and efficacy. In a review of the literature, US Food and Drug Administration advisory committee meeting materials, and company press releases to assess the safety of HBBSs, Natanson and colleagues Article identified 16 randomized clinical trials involving 5 different HBBSs. In a meta-analysis of the data, the authors found that compared with controls, patients who received HBBSs had significantly increased risks of death and myocardial infarction (MI). In an editorial, Fergusson and McIntyre Article discuss the responsibilities of investigators, sponsors, regulatory agencies, and research ethics boards in the planning, review, and conduct of future trials of blood substitutes.