Recent advances in our understanding of the mechanism of action of the synthetic ribonucleoside, ribavirin, have shown that lethal mutagenesis is a viable strategy to combat RNA virus infection.  This method capitalizes on the high mutation rates that occur during normal RNA virus replication and the consequent susceptibility of the virus to extinction by only modest increases in error frequency.  Hence, synthetic compounds that increase the frequency of mutations in the virus genome can effectively reduce the fitness and viability of the virus and confer an antiviral effect.  In order to exploit this vulnerability, we have designed and synthesized a suite of potentially mutagenic ribonucleoside analogues and screened these compounds for antiviral activity against the prototypical RNA virus, poliovirus.  Highlights from our studies will be presented, emphasizing general principles for development of lethal mutagens for use as broad-spectrum antiviral agents.