Following the devastating effects of blood-transmitted human immunodeficiency virus (HIV), blood establishments have become increasingly vigilant for the emergence or re-emergence of new threats to the safety of the blood supply. Many agents have fulfilled the broad definition of emerging blood-transmitted infections, including West Nile virus (WNV), Trypanosoma cruzi, Plasmodium spp., Babesia spp., parvovirus B19, dengue virus, and the prions that cause variant Creutzfeld-Jacob disease (vCJD). Other agents such as human herpes virus-8 (HHV-8-Kaposi's sarcoma virus) and Borellia (Lyme disease) and, perhaps, avian flu virus, are known to have a viremic phase, but have not yet been proved to be transfusion-transmitted. In the wake of these threats, transfusion services use a variety of donor screening interventions, including serologic assays, nucleic acid assays, and geographic exclusions based on potential exposure. The ultimate safeguard may be a pre-emptive pathogen inactivation strategy that will disrupt all nucleic acid-containing agents (though not prions). Considerable effort and resources have been invested in this arena, but currently no single technique is effective for inactivation of both liquid and cellular blood products and toxicity issues have not been completely resolved. The blood supply is remarkably safe with the risk of major pathogens such as hepatitis C virus (HCV) and HIV now reduced to less than one transmission per 2 to 3 million exposures. However, to approach near-zero infectious disease risk for emerging and re-emerging pathogens, new strategies such as pathogen inactivation or multi-pathogen microarray technology will need to be developed or refined.