Even though the oral microbiome is one of the most complex sites on the body it is an excellent model for narrow-spectrum antimicrobial therapy. Current research indicates that disruption of the microbiome leads to a dysbiotic environment allowing for the overgrowth of pathogenic species and the onset of oral diseases. The gram-negative colonizer, Porphyromonas gingivalis has long been considered a key player in the initiation of periodontitis and Streptococcus mutans has been linked to dental caries. With antibiotic research still on the decline, new strategies are greatly needed to combat infectious diseases. By targeting key pathogens, it may be possible to treat oral infections while allowing for the recolonization of the beneficial, healthy flora. In this review, we examine unique strategies to specifically target periodontal pathogens and address what is needed for the success of these approaches in the microbiome era.