Group B Streptococcus (GBS) emerged as the leading cause of newborn infection in the United States in the 1970s. In the 1980s clinical trials demonstrated that giving intrapartum intravenous ampicillin or penicillin to mothers at risk was highly effective at preventing invasive GBS disease in the first week of life (early-onset). In 1996, the first national guidelines for the prevention of perinatal GBS disease were issued; these recommended either antenatal screening for GBS colonization and intrapartum antimicrobial prophylaxis (IAP) to colonized women, or targeting IAP to women with certain obstetric risk factors during labor. In 2002, revised guidelines recommended universal antenatal GBS screening. A multistate population-based review of labor and delivery records in 2003-2004 found 85% of women had documented antenatal GBS screening; 98% of screened women had a colonization result available at labor. However, missed opportunities for prevention were identified among women delivering preterm and among those with penicillin allergy, and more false negative GBS screening results were observed than expected. The incidence of invasive early-onset GBS disease decreased by more than 80% from 1.8 cases/1000 live births in the early 1990s to 0.26 cases/1000 live births in 2010; from 1994 to 2010 we estimate that over 70,000 cases of EOGBS invasive disease were prevented in the United States. IAP effectiveness is similar and high among term (91%) and preterm (86%) infants when first line therapy is received for at least 4h. However, early-onset disease incidence among preterm infants remains twice that of term infants; moreover disease among infants after the first week of life (late-onset disease) has not been impacted by IAP. The US experience demonstrates that universal screening and IAP for GBS-colonized women comprise a highly effective strategy against early-onset GBS infections. Maximizing adherence to recommended practices holds promise to further reduce the burden of early-onset GBS disease. Yet there are also inherent limitations to universal screening and IAP. Some of these could potentially be addressed by an efficacious maternal GBS vaccine.