The burden of early-onset disease caused by group B Streptococcus (GBS) has decreased dramatically in the United States over the past 20 years. Universal culture-based screening at 35 to 37 weeks gestational age and use of intrapartum antibiotic prophylaxis are the cornerstones of prevention measures that have led to this decline. GBS, however, remains the leading cause of early-onset neonatal sepsis in the United States. Revised guidelines for prevention of perinatal GBS are planned for issuance in 2010. This article discusses implementation challenges for clinicians caring for pregnant women and newborns and presents an updated algorithm for neonatal management.