Ribavirin is the first synthetic, broad-spectrum antiviral nucleoside. Despite its more than 30 year history, the mechanism of action of this compound remains unclear and somewhat controversial. Recent data suggest the possibility that the activity of ribavirin against RNA viruses is a reflection of incorporation of ribavirin into the viral genome. Because ribavirin incorporation is not specific, this event leads to lethal mutagenesis of the virus population. The data supporting this new proposal for the mechanism of action of ribavirin are reviewed herein. In addition, we discuss briefly the challenges that remain for development of lethal mutagenesis as an effective antiviral strategy.