Hemophilus influenzae and Staphylococcus aureus (SA) are the predominant pathogens in infants with cystic fibrosis (CF). SA was the major cause of death in the pre-antibiotic era. The reason of the association of SA in CF is unclear. SA causes early damage of the respiratory tract and paves the way for Pseudomonas aeruginosa (PA). Based of this hypothesis, some centers use prophylactic antibiotics, but their efficacy is not proved and may favor growth of PA. Treatment of exacerbations is mandatory. Oral antibiotics are preferred in most cases, although few controlled clinical studies have been reported. Emergence of methicillin-resistant Staphylococcus aureus (MRSA) strains appeared during the recent years. Treatment of MRSA is difficult, patients segregation is discussed.