CD46 is a complement regulator that serves as a cellular pilus receptor for the human pathogens Neisseria gonorrhoeae and Neisseria meningitidis. The role of CD46 in N. gonorrhoeae infection has been further characterized through the identification of domains that are required for bacterial adhesion, as well as the delineation of CD46-dependent signaling responses that promote this adhesion. In addition, the adherence of N. gonorrhoeae to human epithelial cell lines results in cell-surface downregulation followed by the liberation of CD46 into the surrounding milieu. Recently, transgenic mice expressing human CD46 were used in a mouse model of meningitis, in which CD46 enhanced meningococcal traversal of the blood-brain barrier. Although the role of CD46 in infection by the pathogenic Neisseria remains incompletely defined, these advances indicate a dynamic and important contribution of CD46 to Neisseria pathogenesis.