The beginning of the modern era of blood transfusion coincided with World War II and the resultant need for massive blood replacement. Soon thereafter, the hazards of transfusion, particularly hepatitis and hemolytic transfusion reactions, became increasingly evident. The past half century has seen the near eradication of transfusion-associated hepatitis as well as the emergence of multiple new pathogens, most notably HIV. Specific donor screening assays and other interventions have minimized, but not eliminated, infectious disease transmission. Other transfusion hazards persist, including human error resulting in the inadvertent transfusion of incompatible blood, acute and delayed transfusion reactions, transfusion-related acute lung injury (TRALI), transfusion-associated graft-versus-host disease (TA-GVHD), and transfusion-induced immunomodulation. These infectious and noninfectious hazards are reviewed briefly in the context of their historical evolution.