Remarkable improvements have been made in blood safety since the onset of the HIV epidemic. However, the current paradigm does not prevent all transfusion-transmitted infections and is reactive to new agents, thus accepting that some patients may be harmed before preventive measures are introduced. Several methods are now available that selectively damage DNA and RNA, thus inactivating pathogens contaminating blood components while not damaging the cells or plasma proteins of the blood component. Clinical trials have been completed and pathogen-inactivated platelets and plasma are widely used in Europe. A recent consensus conference recommended implementation of pathogen inactivation when a feasible and safe method is available that inactivates a broad spectrum of pathogens. The shortcomings of our present paradigm for preventing transfusion-transmitted diseases are described, along with a summary of the status of pathogen inactivation.