In the 1960s, early onset neonatal sepsis caused by group B Streptococcus (GBS) had an attack rate of 2 per 1000 live births and a 50% fatality rate. Early treatment and then antibiotic prophylaxis were shown to reduce morbidity and mortality rates; however, GBS remains a leading cause of perinatal infection. This article will review our investigations and related studies, including our studies in monkeys, that have contributed to current diagnosis, treatment, and prevention of disease caused by GBS. Although it has not been possible to eradicate GBS colonization, intravenous antibiotic prophylaxis given during parturition has been effective in the prevention of vertical transmission in animals and humans. Recently, diagnostic tests with polymerase chain reaction have offered promise for rapid accurate detection. This could lead to a major shift in the timing of diagnosis from the office setting to delivery suite. The potential for immunization remains a challenge.