While mutation is the driving force behind evolution, most mutations are detrimental; therefore, elevating the mutation rate of a virus should diminish fitness. Because riboviruses and retroviruses have high mutation rates, a small increase in their mutation rates could exceed their threshold of viability. This approach, elevation of the viral mutation rate beyond the threshold of viability, extinction catastrophe or lethal mutagenesis, was proposed over a decade ago as a novel chemotherapeutic strategy. Extinction catastrophe induced by promutagenic nucleosides has been demonstrated in cell culture models, but most mutagens are carcinogenic and are poorly tolerated. Thus, clinical translation of viral mutagens has been difficult, casting doubt on the clinical viability of this strategy. This Perspective covers recent advances in the use of promutagenic nucleosides and the Vif-APOBEC interaction as chemotherapeutic strategies for targeting viral mutation rates.