As a result of continuous improvement efforts, the blood supply is now extremely safe. However, emerging infections offer a real or potential challenge to such safety. Since 2003, two new tests have been implemented in the United States in order to reduce the risk of transfusion transmission of West Nile virus and Trypanosoma cruzi. In addition, Babesia microti and dengue viruses are considered to be high-priority threats. Q fever outbreaks in the Netherlands illustrate a localized threat that has been assessed and managed through human and agricultural public health measures and by selective testing of blood donors. The recently recognized gammaretrovirus XMRV has generated scientific and social controversy and illustrates a number of problems in managing blood safety policy.