Infections of the head and neck, especially those of odontogenic origin, are among the oldest conditions treated by our surgical specialty. Despite all interventions many patients have suffered dire consequences. Elimination of infection by removal of the source is an ancient surgical concept; however, the development of local and general anesthesia have facilitated painless surgery. The two basic principles of infection management—establishing drainage and removing the source—received a boost from the discovery of the “wonder drug” penicillin by Alexander Fleming in 1928 (although it was not used until the 1940s). In spite of the monumental discovery of antibiotics, the principal treatment of odontogenic infections remains surgical, and except for historic advances in preventative measures (such as water fluoridation), this is unlikely to change in the foreseeable future. Further identification of the oral microbial flora in parallel with the constant but often lagging discovery of new and improved antibiotics has resulted in an ongoing battle between antimicrobial resistance and microbiologists. The identification of nonbacterial (e.g., viral, fungal) infections affecting the head and neck, especially in the immunocompromised patient, has and continues to challenge our profession.