Short sequence repeats (SSRs), also known as variable number of tandem repeats or micro-satellites, are inherently unstable entities that undergo frequent variation in the number of repeated units through slipped strand mispairing during DNA synthesis. In humans, unit number variability in SSRs has been associated with the occurrence of specific genetic diseases, whereas in micro-organisms SSRs have been elegantly linked to modulation of gene expression. Knowledge of the functional constraints imposed upon the SSRs sheds light on their potential use as molecular clocks for monitoring microbial genome evolution. Although microbial SSR genotypes have been used with increasing frequency for studying the epidemiology and evolution of microbial strains and isolates, such approaches should be used with caution.