RNA viruses, for many reasons, have evolved to be highly mutable, and as such readily escape antiviral drugs and other compounds designed to limit viral infections. The quasispecies theory purports that this ability to escape is due (at least in part) to the fact that viral populations contain an interactive collection of unique viruses, each with slightly different genomic mutations which could potentially afford that virus resistance. Poliovirus, a plus-stranded RNA virus, has previously been shown to be sensitive to treatment with both the nucleoside analog ribavirin and to poliovirus specific siRNA. We show in these studies, that poliovirus is capable of mutating to escape the antiviral affects of both of these compounds. Interestingly, ribavirin-resistant escape mutants (G64S) were shown to have an RNA-dependent RNA polymerase (RdRp) with higher fidelity than that of wildtype virus. G64S virus populations were shown to have a narrow quasispecies and had limited neurovirulence in an infectious mouse model, thereby supporting the quasispecies theory and suggesting a link between mutation rate, population dynamics and pathogenesis. Further studies showed that poliovirus was able to effectively escape the affects of both siRNA and antisense morpholino oligomers (PPMO). Treatment with a pool of siRNA prevented poliovirus escape however, while treatment with two PPMO was much more effective at reducing viral titers than treatment with one PPMO. Furthermore, treatment of poliovirus infected mice with a PPMO (EnteroX) targeting a region of the poliovirus genome shown to be conserved amongst all Enteroviruses and Rhinoviruses, decreased viral titers in infected tissues and protected infected mice from paralysis and death. Taken together, these studies suggest that treatments which are designed to both disrupt quasispecies populations (mutagens), and target multiple specific regions within the virus, may be effective strategies for limiting RNA virus infections.