We present a review of the current status of the use of methylene blue (MB) photoinactivation of viruses starting with the first early observations up to its current use to inactivate HIV-1 in blood products. Basic mechanism of action studies conducted with model bacteriophages indicate that MB-photomediated viral RNA-protein crosslinkage is a primary lesion and that oxygen, specifically singlet oxygen, is very important also. Basic studies on the mechanism of action with HIV are lacking; however, we do show new data illustrating that viral reverse transcriptase inactivation per se cannot account for MB-mediated photoinactivation. We also show data illustrating that MB photomediates the inactivation of West Nile Virus, a flavivirus, which poses a significant new threat to the continental US. MB photoinactivation of viruses show significant promise because the technology not only offers significant potency but the history of safe MB use in human therapy makes it attractive also.