Escherichia coli (E. coli) is a gram-negative organism that commonly colonizes the gastrointestinal tract and has the ability to travel hematogenously to the central nervous system, resulting in inflammation of the brain and spinal cord membranes. E. coli meningitis is a significant cause of mortality and morbidity in neonates and infants throughout the world and is less common in adults. E. coli meningitis has a high degree of bacteremia and invasion of the blood-brain barrier with specific microbial and host factors as well as microbe- and host specific signaling molecules. The blocking of microbial and host factors that contribute to E. coli invasion of the blood-brain barrier is shown to be efficient in preventing E. coli penetration into the brain. It is critical to outline current in vitro and in vivo models to understand the pathogenesis of E. coli meningitis and to further refine diagnostic workup and treatment plans.