Nucleic acid testing (NAT) holds the promise of closing the window of infectiousness for hepatitis C virus (HCV) and the human immunodeficiency virus (HIV) in the general blood supply. Pioneering work by the source plasma industry with NAT for hepatitis A virus (HAV), hepatitis B virus (HBV), and parvovirus B19 suggests that, in the future, the risk of other viral infections may be reduced using similar technology. The European Commission decree that, by July 1999, all source plasma for fractionation should be NAT nonreactive for HCV at a sensitivity of 100 viral IU/mL, has driven the implementation of NAT in the United States. It is estimated that more than 95% of the US blood supply is currently tested by one of two investigational tests for HCV and HIV, and many institutions restrict the release of red blood cell (RBC) and plasma products prior to the release of NAT results. NAT implementation has been hampered by a lack of fully automated, low-cost technologies; the absence of Food and Drug Administration (FDA)-approved and validated clinical tests; and lagging turnaround times. Results from US investigational trials of the Procleix Transcription Mediated Amplification (TMA) HCV/HIV (Chiron Corp, Emeryville, CA) and the COBAS AmpliScreen (Roche Diagnostics, Indianapolis, IN) polymerase chain reaction (PCR) assays have begun to substantiate their value. While NAT assays will not replace serologic tests, they lay the groundwork for further reducing the already low risk of infection transmission through transfusion of blood components and their factor derivatives.