Serological assays, which have been implemented over the past five decades, have proven to be effective for screening out donors who are chronically infected with the classic transfusion-transmitted infectious diseases (TTIDs), such as syphilis, hepatitis B virus, human immunodeficiency virus, hepatitis C virus, and human T-cell leukemia-lymphoma virus types I and II. However, over the past 15 years nucleic acid amplification technology (NAT) screening has proven to be the preferred option for detection of many emerging infectious diseases (EIDs) that generally cause acute infections. These EIDs include parvovirus B19, hepatitis E virus, babesia, and multiple transfusion-transmitted arboviruses, such as West Nile, dengue, chikungunya, and Zika. Such infections are effectively interdicted by NAT, whereas serological testing is ineffective and would detect high rates of donors with resolved infections. This session will review the evolution of responses to TTIDs, with a focus on the global Zika virus epidemic, and will highlight why ongoing surveillance for and rapid response to EIDs, optimally with sensitive multiplexed NAT assays, is critical to maintaining global blood safety.