Spontaneous mutations are the ultimate source of all natural genetic variation upon which evolution depends. Recent observations have revealed that many genes are associated with mutation-prone DNA tracts, each consisting of a simple motif repeated over and over in tandem. These simple sequence repeats (SSRs) may provide a previously unrecognized source of abundant quantitative genetic variation based on mutations that are frequent, site-specific and reversible, yet seldom substantially deleterious. Such sequences may be evolutionarily significant, equipping genomes and individual genes with adjustable ‘tuning knobs’ for efficient adaptation.