In July 2008, a workshop sponsored by the Division of Blood Diseases and Resources of the National Heart, Lung, and Blood Institute (NHLBI) was convened to identify potential research opportunities that could advance our understanding of both the biologic and the clinical impact of the various available pathogen reduction/inactivation (PR/PI) methods of blood components (platelets [PLTs], red blood cells, and plasma) intended for allogeneic transfusion. These discussions resulted in consensus that, even though several PR/PI technologies have already been licensed and are being used in Europe and elsewhere for PLTs and plasma, concerns about possible side effects, particularly component quality and pulmonary toxicity, have impeded regulatory approval in North America (United States and Canada). Such concerns thus threaten to stall further development of these technologies. As a consequence, the NHLBI workshop participants focused on formulating a series of research-related recommendations to better understand, mitigate, and prevent these adverse effects. Other important issues identified included the need for a single method to inactivate pathogens in whole blood without damaging the various blood components; new ways to monitor the efficacy of treated components, including animal models to screen for safety; a better understanding of the effect of PR/PI-treated products on recipient alloimmunization, tolerance, and immune modulation; understanding the impact of PR/PI on various other noninfectious hazards of transfusion; and establishing methods to evaluate risk-benefit and cost-effectiveness, in particular with reference to emerging pathogens. The working group also discussed issues related to specific blood components, such as improving the process of clinical evaluation, investigating the impact of PR/PI on component storage lesions, understanding mechanisms that reduce component viability, and addressing the underlying resistance to the adoption of PR/PI-treated components. This communication summarizes the opinions of workshop participants on these issues and concludes with a list of areas for possible research that could advance the application of PR/PI methods to enhance the safety of the world's blood supplies.