Pathogen-reduction (inactivation) provides a proactive approach to reducing transfusion-transmitted infection. Pathogen-reduction technologies have been successfully implemented by plasma fractionators resulting in no transmission of human immunodeficiency, hepatitis C, or hepatitis B viruses by US-licensed plasma derivatives since 1987. Fractionation technologies cannot be used to treat cellular blood components. Although blood donor screening, deferral and disease testing have drastically reduced the incidence of transfusion-transmitted diseases, the threat of new or re-emerging pathogens remains. Of particular concern is the silent emergence of a new agent with a prolonged latent period in which asymptomatic infected carriers would donate and spread infection. The ultimate goal of pathogen-inactivation is to reduce transmission of potential pathogens without significantly compromising the therapeutic efficacy of the cellular and protein constituents of blood. The acceptable technology must not introduce toxicities into the blood supply nor result in neoantigen formation and subsequent antibody production. Several promising pathogen-inactivation technologies are being developed and tested, and others are currently in use, but all of them have limits. Pathogen-reduction promises an additional 'layer of protection' from infectious agents and has the potential to impact the safety of blood transfusions worldwide.