The mortality and morbidity associated with bacterial meningitis have remained significant despite advances in antimicrobial chemotherapy and supportive care. A major contributing factor is the incomplete understanding of the pathogenesis of this disease. For example, most cases of bacterial meningitis develop as a result of hematogenous spread, but it is unclear how circulating bacteria cross the blood-brain barrier (12, 25, 33, 46). Recent studies have shown that Escherichia coli K1, group B Streptococcus, Streptococcus pneumoniae, and Citrobacter spp., the important pathogens that cause meningitis, translocate from blood to the central nervous system (CNS) without altering the integrity of the blood-brain barrier (2, 23, 27, 36, 42). These studies of bacterial translocation from blood to the CNS have become possible because of the availability of both in vitro and in vivo models of the blood-brain barrier (1, 3, 4, 7, 11, 13, 17–20, 22, 26, 28, 32, 41, 43, 47). The in vitro model of the blood-brain barrier is composed of brain microvascular endothelial cells (BMEC), which exhibit transendothelial resistance of 200 to 600/cm2, a unique property of the brain microvascular endothelium monolayer compared to systemic vascular endothelium. The in vivo model of the blood-brain barrier utilizes experimental hematogenous meningitis in animals. In these experimental meningitis models, bacteria are injected via intravenous, intraperitoneal, subcutaneous, or intracardiac administration, resulting in bacteremia and subsequent entry into the CNS. At present, E. coli-BMEC interactions represent the most characterized system concerning how circulating bacteria cross the blood-brain barrier. This review summarizes our current understanding of the pathogenetic mechanisms involved in bacterial translocation of the bloodbrain barrier, using E. coli as a paradigm.