The blood supply is safer than it has been at any other time in recent history, and, in the context of other health care-related adverse events, the risks associated with blood transfusion are extremely small. The current high level of safety is the result of successive refinements and improvements in how blood is collected, tested, processed, and transfused; nonetheless, blood and plasma products remain vulnerable to newly identified or reemerging infections. In recent years, numerous infectious agents-including several newly discovered hepatitis viruses, the agents of transmissible spongiform encephalopathies, and tickborne pathogens-have been identified as potential threats to the safety of blood and plasma. Continued vigilance is critical to protect the blood supply from known pathogens and to monitor for the emergence of new infectious agents. Recent terrorist activities in the United States add new considerations to maintaining the safety and supply of blood. Education of clinicians and patients regarding the benefits and risks associated with the judicious use of blood and blood products can assist in informed decision making.