Foot-and-mouth disease virus (FMDV) is genetically and phenotypically variable. As a typical RNA virus, FMDV follows a quasispecies dynamics, with the many biological implications of such a dynamics. Mutant spectra provide a reservoir of FMDV variants, and minority subpopulations may become dominant in response to environmental demands or as a result of statistical fluctuations in population size. Accumulation of mutations in the FMDV genome occurs upon subjecting viral populations to repeated bottleneck events and upon viral replication in the presence of mutagenic base or nucleoside analogs. During serial bottleneck passages, FMDV survive during extended rounds of replication maintaining low average relative fitness, despite linear accumulation of mutations in the consensus genomic sequence. The critical event is the occurrence of a low frequency of compensatory mutations. In contrast, upon replication in the presence of mutagens, the complexity of mutant spectra increases, apparently no compensatory mutations can express their fitness-enhancing potential, and the virus can cross an error threshold for maintenance of genetic information, resulting in virus extinction. Low relative fitness and low viral load favor FMDV extinction in cell culture. The comparison of the molecular basis of resistance to extinction upon bottleneck passage and extinction by enhanced mutagenesis is providing new insights in the understanding of quasispecies dynamics. Such a comparison is contributing to the development of new antiviral strategies based on the transition of viral replication into error catastrophe.