Central nervous system (CNS) infections continue to be an important cause of morbidity and mortality. Microbial invasion and traversal of the blood–brain barrier is a prerequisite for CNS infections. Pathogens can cross the blood–brain barrier transcellularly, paracellularly and/or in infected phagocytes (the so-called Trojan-horse mechanism). Consequently, pathogens can cause blood–brain barrier dysfunction, including increased permeability, pleocytosis and encephalopathy. A more complete understanding of the microbial–host interactions that are involved in microbial traversal of the blood–brain barrier and the associated barrier dysfunction should help to develop new strategies to prevent CNS infections.