Staphylococcus aureus is a continuously evolving and formidable pathogen that has been a problem for both healthy and sick neonates for decades. Much focus over the past 20 years has been on hospital-associated methicillinresistant S aureus (HA-MRSA); however, a global epidemic because of virulent community-associated MRSA (CA-MRSA) that has no “fitness cost” for carrying antibiotic-resistance genes has moved into neonatal intensive care units (NICUs). Recently, methicillin-susceptible S aureus has adopted some of the virulence factors of CA-MRSA and is an increasingly common cause of hospital-acquired infections in NICUs. This article reviews the changing epidemiology, clinical manifestations, and treatment of S aureus in neonates.