The RNA viruses replicate as complex distributions of closely related genomes termed viral quasispecies. The behavior of the evolving quasispecies and its response to selective pressures such as antiviral treatment is influenced by the ensemble of mutants that compose the viral population. One such influence is the presence of minority subpopulations in the mutant spectra of viral quasispecies. Biologically relevant mutants have long been known to be present as minority components of replicating viral populations. However, experiments designed with specific mutants of the animal pathogen foot-and-mouth disease virus in cell culture explained the presence of a class of minority genomes termed memory genomes. They descend from those variants that were dominant at an earlier phase of quasispecies evolution, and arise as a consequence of quasispecies dynamics, when viral populations are subjected to discontinuous selective pressures. The presence of memory genomes has also been documented during intrahost evolution of HIV-1 in vivo. The analysis of sequential viral samples of different HIV-1-infected patients showed that two distinct types of memory can operate in retroviruses: a replicative memory analogous to that observed in foot-and-mouth disease virus, as well as a reservoir memory derived from the integrative phase of the retroviral lifecycle. Despite being hidden as minority components of the HIV-1 viral population (ranging from about 0.1 to 20% of the total number of genomes in the quasispecies analyzed), memory genomes can drive the evolution of the virus during HIV-1 infections under antiviral therapy. The limited availability of current experimental data on minority HIV-1 subpopulations in vivo implies that further studies are required in order to define the cutoffs of clinically relevant minority genomes. Nevertheless, it is already evident that such low-abundance genomes remain undetectable by traditional genotyping methods such as consensus sequencing or conventional hybridization techniques. Several experimental systems are currently available for the detection and characterization of minority components of the mutant spectra of viral quasispecies including HIV, hepatitis C virus and hepatitis B virus. Some of these biotechnological approaches could, in the near future, be taken over and exploited in the clinical setting as useful biosensors with which to improve the management of HIV-infected patients.