A major contributing factor to high mortality and morbidity associated with bacterial meningitis is the incomplete understanding of the pathogenesis of this disease: It is unclear how circulating bacteria cross the blood-brain barrier (BBB). Recent studies with Escherichia coli K1 show that successful traversal of the BBB requires a high degree of bacteremia, invasion of brain microvascular endothelial cells (BMEC), host cell actin cytoskeleton rearrangements and related signaling pathways, and traversal of the BBB as live bacteria. Several microbial determinants such as the K1 capsule, OmpA, Ibe proteins, AslA, TraJ, and CNF1 contribute to BMEC invasion. Of interest, E. coli K1 trafficking mechanisms differ from those of other meningitis-causing bacteria such as Listeria monocytogenes and group B streptococcus. Complete understanding of bacteria-BMEC interactions contributing to translocation of the BBB should assist in developing novel strategies to prevent bacterial meningitis.