Staphylococcus aureus is a frequent agent of serious intensive care unit infections with high associated mortality rates. Resistance to methicillin is frequent, exceeding 50% in many countries, and for these strains, vancomycin is the agent of choice. Resistance to this drug is now frequent for Enterococcus, but low rates are reported for S. aureus. Nonetheless, treatment failures with vancomycin for infections caused by strains considered susceptible have been reported during recent years. This article aims to review the possible explanations for this phenomenon, which is challenging the old paradigm of S. aureus infections and vancomycin use.