Although improved donor selection criteria and tests of increasing sensitivity have dramatically reduced the risks of transfusion-transmitted infectious disease, multiple potential means exist for a pathogen to escape detection and injure a recipient: a window period remains in which an infectious donor cannot be detected; some transmissions (e.g. bacterial contamination of platelets) have detection methods that are far from the desired capabilities; and ‘emerging’ pathogens continue to represent a risk to recipients until effective testing strategies are developed and implemented. Pathogen inactivation of labile blood components represents a means of addressing all three of these shortcomings simultaneously as they have for plasma derivatives. Multiple effective means of pathogen inactivation have been validated and put into use for plasma and for platelet components. While not yet universally implemented, these appear to have an acceptable toxicity profile and retain a clinically useful – although slightly diminished – degree of efficacy that is not associated with increased usage. Some of these techniques, such as solvent–detergent treatment of plasma, appear to offer benefits beyond avoidance of infectious disease; in this case, the pooling involved in the process, while creating a risk for dissemination of non-enveloped viruses, appears to reduce the risk of TRALI considerably. Promising systems for pathogen inactivation of red blood cells and whole blood are under development and would complete the spectrum of treatment across all labile components. While some jurisdictions, most notably the United States, interpret the completed clinical trials as not yet presenting adequate benefit to balance perceived risks, the primary impediments to implementation would appear to fall more into the logistic than scientific category. Is there sufficient benefit to warrant implementation of pathogen inactivation for plasma and platelets before red cell treatment is feasible? How can the processes be accomplished while minimizing cost to the system? How will each country’s healthcare system accommodate the inevitably increased expense for this additional production step? What impact will a fully pathogen-inactivated blood supply have on clinicians’ conception of transfusion risk and thus blood utilization? This review provides an overview of data available from clinical trials and attempts to identify a path towards improving transfusion recipient safety.