Despite improved pretransfusion donor evaluation and testing, there is still residual risk of transfusion-associated viral infectious disease. Moreover, other important infectious pathogens, including bacteria, protozoa, and nonenveloped viruses, are not detected in current testing programs. Recent investigations from several laboratories have stimulated interest in decontamination of blood products as an additional means to further enhance the safety of blood transfusion. Furthermore, because testing is a retrospective strategy, a robust decontamination process could provide prospective protection against new pathogens that may enter the blood donor population. Recent advances in decontamination of fresh frozen plasma, plasma derivatives, platelet concentrates, and erythrocytes are reviewed. The introduction of solvent-detergent-treated plasma fractions marks an important advance in transfusion safety. Other technologies for cellular components are emerging to address transfusion-associated infectious disease transmission.