Neisseria is a highly adapted human specific pathogen that initiates infection at the mucosal epithelia by using multiple adhesins to interact with host cell receptors. Colonization begins at the apical cell surface with a multi-step adhesion cascade, followed by invasion and persistence within the cell and finally transcytosis at the basolateral surface. The type IV pill are implicated in mediating the initial attachment of both meningococci and gonococci, and this association has been shown to involve contact with the cellular receptor CD46. In this review we describe the initial events in the adhesion, invasion and signaling of pathogenic Neisseria focusing on the initial attachment and signaling induced by the interaction of the type IV pili with CD46.