Because natural selection is commonly presumed to minimize mutation rates, the discovery of mutationally unstable simple sequence repeats (SSRs) in many functional genomic locations came as a surprise to many biologists. Whether such SSRs persist in spite of or because of their intrinsic mutability-whether they constitute a genetic burden or an evolutionary boon--remains uncertain. Two contrasting evolutionary explanations can be offered for SSR abundance. First, suppressing the inherent mutability of repetitive sequences might simply lie beyond the reach of natural selection. Alternatively, natural selection might indirectly favor SSRs at sites where particular repeat-number variants have provided positive contributions to fitness. Indirect selection could thereby shape SSRs into "tuning knobs" that facilitate evolutionary adaptation by implementing an implicit protocol of incremental adjustability. The latter possibility is consistent with deep evolutionary conservation of some SSRs, including several in genes with neurological and neurodevelopmental function.