Until the late 1960s, penicillin was considered optimal antibiotic therapy for meningitis secondary to Streptococcus pneumoniae and some staphylococcal species. Beginning with the earliest reports in the late 1960s, there has been increasing recognition of penicillin-resistant pneumococcal and staphylococcal meningitis. For many years cefotaxime and ceftriaxone, broad-spectrum cephalosporins, were adequate to treat most strains of these penicillin-resistant bacteria. However, with the advent of strains of pneumococcus that had even higher levels of penicillin resistance, alternative therapies were sought. Vancomycin is one of the most effective alternative antibiotics for penicillin- and cephalosporin-resistant pneumococcal meningitis. It has also been a mainstay of therapy for methicillin-resistant Staphylococcus aureus. The problem with using vancomycin to treat meningitis lies in its erratic penetration of the blood–brain barrier (BBB). Evidence from both animal models and human patients consistently demonstrates that when vancomycin is administered intravenously, only about 10% of the serum level is found in the cerebrospinal fluid (CSF). Inflammation within the meninges seems to play a role in inhibiting crossing of the BBB. The use of steroids in the acute treatment of meningitis has become more prevalent in light of recent evidence in both children and adults that steroid use acutely lessens the burden of neurologic sequelae. However, the use of steroids also seems to limit the amount of vancomycin that passes through the BBB. As an example, in animal models, the addition of dexamethasone has been found to lower the concentration of vancomycin in the CSF. Either through stabilization of the BBB by decreasing inflammation or through some other mechanism, penetration of the BBB by vancomycin is impaired.