While S. aureus small colony variants (SCVs) have been recognized in clinical materials for decades, only recently have these strains been linked to persistent, resistant, and relapsing infections. The biochemical basis for this phenotype appears to be reduced electron transport, which leads to many changes in these organisms, including decreased alpha-toxin production. Reduced alpha-toxin has been found to facilitate bacterial survival within cultured endothelial cells. This SCV subpopulation is more resistant to antibiotics, grows very slowly, and demonstrates unusual colony morphology. Hence, these resistant strains can be easily overloaded in the clinical microbiology laboratory, and may be resistant to conventional antibiotic therapy. Clinicians should ask the laboratory to search for SCVs with relapsing and resistant S. aureus infections.