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Aggregatibacter actinomycetemcomitans, a member of the Gram-negative taxonomic family Pasteurellaceae, has attracted considerable attention as a potentially important pathogen in specific forms of periodontal disease and has earned a reputation as a member of the HACEK group of bacteria associated with some cases of infective endocarditis. The bacterium has acquired an impressive virulence-related armamentarium, including two well-characterized cytotoxins, exoenzymes, adhesins, and signaling molecules that promote its colonization and the perturbation of the tissues, structural cells, and inflammatory cells of the human oral cavity. This Special Issue focuses on the properties and activities of A. actinomycetemcomitans that promote its function as an infectious agent, that is, its ability to target specific host populations and define its interactions with specific mucosal tissues and cells. The objective is to present a complete picture of the participation of this bacterium in disease by presenting both in vitro and in vivo experimental and clinical studies. A comprehensive view of the contribution of this bacterium to the mechanisms of infection and disease should also provide a basis for the development of new control strategies that move beyond the classical antibiotics.