PURPOSE OF REVIEW Neonatal Escherichia coli meningitis continues to be an important cause of mortality and morbidity throughout the world. The major contributing factors to this mortality and morbidity include our incomplete knowledge on its pathogenesis and an emergence of antimicrobial-resistant E. coli. Recent reports of neonatal meningitis caused by E. coli producing CTX-M-type or TEM-type extended-spectrum β-lactamases create a challenge, and innovative approaches are needed to identify potential targets for prevention and therapy of E. coli meningitis. RECENT FINDINGS E. coli invasion of the blood-brain barrier is a prerequisite for penetration into the brain and requires specific microbial-host factors as well as microbe-specific and host-specific signaling molecules. Recent studies identified additional microbial and host factors contributing to E. coli invasion of the blood-brain barrier and elucidated their underlying mechanisms. Blockade of the microbial-host factors contributing to E. coli invasion of the blood-brain barrier was shown to be efficient in preventing E. coli penetration into the brain. SUMMARY Continued investigation on the microbial-host factors contributing to E. coli invasion of the blood-brain barrier is needed to identify new targets for prevention and therapy of E. coli meningitis, thereby limiting the exposure to emerging antimicrobial-resistant E. coli.