Enterovirus populations display quasispecies dynamics, characterized by high rates of mutation and recombination, followed by competition, selection, and random drift acting on heterogeneous mutant spectra. Direct experimental evidence indicates that high mutation rates and complex mutant spectra can serve for the adaptation of enteroviruses to complex environments. Studies with the RNA-dependent RNA polymerase of picornaviruses suggest that multiple enzyme sites may influence the template-copying fidelity (incorporation of incorrect vs correct nucleotide) during RNA replication. Mutation and recombination are an unavoidable consequence of the molecular mechanisms inherent to the process of viral genome replication and underlie the diversification of enterovirus genomes as they multiply in human and animal hosts. The diversity of disease manifestations associated with closely related enteroviruses is probably attributable to profound biological effects of some mutations that, because of their limited number, do not necessarily affect the phylogenetic position of the virus. The combination of highly dynamic mutant spectra with unpredictable alterations of biological behavior by minimal genetic change defies classical classification schemes. The result is the need to update the grouping of enteroviruses quite frequently into genetic and serological types and subtypes. The tolerance of enterovirus genomes to remain replication-competent despite multiple mutation and recombination events encourages the engineering of live-attenuated vaccines. Also, the application of quasispecies theory to an understanding of the limits of viral genomes to accept mutations, together with an increasingly deeper understanding of the mechanisms of mutagenesis by nucleoside analogs, has paved the way for the application of lethal mutagenesis as a new antiviral strategy.