Staphylococcus aureus small colony variants (SCVs) have been found to cause persistent and antibiotic-resistant infections in humans. Persistence seems to relate to the ability of SCVs to reside within host cells without lysing them. The lytic activity of S. aureus arises from the production of α-toxin, and SCVs are non-α-toxin-producing. The biochemical basis for the SCV phenotype has been linked to decreased electron transport which leads to reduced α-toxin production. Electron transport is diminished due to blocks in either haemin or menadione biosynthesis, which results in the loss of the menaquinone or cytochrome components of the electron transport chain, respectively. Reduction in electron transport activity also causes reduced coagulase production, decreased pigmentation, and reduced aminoglycoside uptake. The decreased uptake of aminoglycosides comes from the weaker electrochemical gradient across the cell membrane. The SCVs are not only more resistant to the positively charged aminoglycosides, but they are also resistant to several other positively charged antistaphylococcal compounds: protamine, some L-antibiotics, and platelet microbicidal proteins. The multiple phenotypic changes, such as decreased haemolytic activity (α-toxin), decreased coagulase activity, reduced pigmentation, and slow growth, make the SCVs difficult to recognize as S. aureus. Finally, the intracellular milieu of the mammalian cell enhances the production of SCVs. Of interest, a number of other genera (both Gram-positive and Gram-negative) also produce electron transport SCVs that are resistant to aminoglycosides, hence the observations with S. aureus may apply to other types of organisms. Thus, the SCV phenotype allows S. aureus to persist within host cells and resist antimicrobial agents, and the atypical colonial morphology may lead to misidentification of these organisms. Because many of the SCVs are menadione auxotrophs, the addition of vitamin K to the medium increases the activity of antibiotics against these variants which might prove to be a valuable therapeutic adjunct.