Abstract This chapter reviews the pathogenesis of Haemophilus influenzae type b (Hib) meningitis, a multistep process that begins with: (i) colonization of the nasopharynx; (ii) subsequent invasion into the blood, which leads to haematogenous dissemination; (iii) bacterial penetration of the blood-cerebrospinal fluid barrier/blood-brain barrier and entry into the subarachnoid space; which leads to (iv) a compartmentalized host inflammatory response. A newborn rat model for Hib meningitis is proposed, which is based on current knowledge of bacterial virulence factors and host cell receptor recognition of these ligands.