The PROCLEIX West Nile virus (WNV) assay is based on transcription-mediated amplification and is the most sensitive nucleic acid test commercially available today for blood screening. Since 2003, in the USA, the assay has been used for year-round screening of blood donations in minipools of 16 and in an individual-donation testing format, when appropriate triggering guidelines for such switch become effective. The test can be run on the semiautomated PROCLEIX modular platform or the fully-automated PROCLEIX TIGRIS System. This assay and the corresponding platforms have been developed and are manufactured by San Diego-based Gen-Probe, Inc., while they are marketed and distributed by Chiron, a Novartis business. This review covers some of the epidemiological and virological aspects of WNV, as well as clinical questions and technological assessment of the transcription-mediated amplification and alternative technologies used in WNV blood screening.