Despite the implementation of highly sensitive methods for the detection of pathogens in donor blood products, the risk of transmission of infectious disease to transfusion recipients remains. Of greatest concern, and accounting for most of the risk, are newly-emerging pathogens for which screening assays do not yet exist or well-known pathogens for which testing regimens are not routinely employed. Furthermore, passive donor screening programs are unlikely to capture all potentially infective donors. A promising strategy to overcome these limitations is the proactive incapacitation of pathogens residing in donor units. Several unique pathogen reduction/inactivation (PR/PI) platforms have been developed and implemented in clinical settings. The aims of this article are to review: (1) the basic methodology underlying PR/PI platforms, (2) the potential toxicities associated with PR/PI treatment of blood products, and (3) the data and outcomes from clinical trials involving currently available PR/PI platforms.