Blood transfusions are life-saving therapies; however, they can result in adverse events that can be infectious or, more commonly, noninfectious. The most common noninfectious reactions include febrile nonhemolytic transfusion reactions, allergic transfusion reactions, transfusion-associated circulatory overload, transfusion-related acute lung injury, and acute and delayed hemolytic transfusion reactions. These reactions can be asymptomatic, mild, or potentially fatal. There are several new methodologies to diagnose, treat, and prevent these reactions. Hemovigilance systems for monitoring transfusion events have been developed and demonstrated decreases in some adverse events, such as hemolytic transfusion reactions. Now vein-to-vein databases are being created to study the interactions of the donor, product, and patient factors in the role of adverse outcomes. This article reviews the definition, pathophysiology, management, and mitigation strategies, including the role of the donor, product, and patient, of the most common noninfectious transfusion-associated adverse events. Prevention strategies, such as leukoreduction, plasma reduction, additive solutions, and patient blood management programs, are actively being used to enhance transfusion safety. Understanding the incidence, pathophysiology, and current management strategies will help to create innovative products and continually hone in on best transfusion practices that suit individualized patient needs.