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Staphylococcus aureus is one of the first and most common pathogens to be isolated from the respiratory tract of patients with cystic fibrosis. The prevalence of respiratory tract colonization/infection with both methicillin-susceptible and methicillin-resistant S. aureus has increased over the past decade. The clinical significance of colonization/infection with these pathogens is variable, leading to numerous therapeutic strategies: primary prophylaxis, eradication, treatment of cystic fiboris pulmonary exacerbations, and treatment of methicillin-resistant S. aureus.Studies have demonstrated increased prevalence of S. aureus in clinical laboratories that use selective media. Additionally, small colony variant S. aureus has been associated with persistent infection, co-infection with Pseudomonas aeruginosa, and frequent courses of antibiotics, but this phenotype may be difficult to identify in clinical laboratories. Increased prevalence of methicillin-resistant S. aureus has led to use of oral and inhaled antibiotics in attempts to eradicate this pathogen; these studies have yielded variable results.The epidemiology of S. aureus in cystic fibrosis has changed. Studies are needed to assess the clinical significance of the increased prevalence of both methicillin-susceptible and methicillin-resistant S. aureus, and whether primary prophylaxis or new treatment/eradication protocols are effective.