Small colony variants (SCVs) are now recognized as an important problem under selected circumstances. Staphylococcal SCVs have been most extensively studied, but SCVs occur in many other species [Proctor RA et al. Nature Microb Rev 4: 295, 2006]. One of the hallmarks of staphylococcal SCVs is resistance to antibiotic therapy when the parent isolate is susceptible in vitro. This occurs because the parent isolates are found, yet the SCVs are easily missed with routine clinical laboratory testing. In addition, Staphylococcus aureus SCVs are primed for entry into and survival within host cells, thereby shielding them from host defenses. One should also suspect SCVs when late recurrence occurs. S. aureus SCVs form more biofilm and generally induce a less vigorous host inflammatory response. Finally, SCVs should be sought when mixed cultures are reported as S. aureus SCVs can masquerade as streptococci and coagulase negative staphylococci due to the presence of small non-hemolytic colonies and their atypical biochemical profiles. Not infrequently, an initial report will be for a non-S. aureus strain, then further testing leads to a later report that S. aureus is present. The mechanisms for these phenomenon will be discussed.