Staphylococci have various strategies for resisting therapy that extend beyond classic mechanisms. Clinical experience with device-associated infections as well as with infections due to small-colony variants (SCVs) clearly shows that both antibacterial chemotherapy and host defense mechanisms are often unable to eliminate the pathogens and cure these infections. Of particular interest is the fact that in the past few years an increasing number of various foreign body-related infections due to staphylococcal SCVs have been reported. In this overview, the characteristics of SCVs recovered from clinical specimens and of defined mutants displaying the SCV phenotype are described. Their slow growth and changing biochemical and physiological features represent a challenge to clinical laboratory personnel, because recovery, identification, as well as susceptibility testing of these variants need particular efforts. In addition, the reduced susceptibility to aminoglycosides and the ability of SCVs to persist intracellularly require specific attention for the treatment of these infections. Thus, special efforts to search for these variants formed by Staphylococcus aureus or by coagulase-negative staphylococci should be considered when an infection is particularly resistant to therapy, persists for a long period or fails to respond to apparently adequate therapy with antimicrobial compounds.