The purpose of this review is to provide the clinician with some practical rationale for the selection and use of antibiotics in the treatment of destructive periodontal diseases. We have attempted to integrate approximately 20 years of periodontal literature describing antibiotic therapy with personal experience and 21st century ideas. This article addresses antibiotic use during treatment of aggressive periodontitis with emphasis on juvenile disease and adult refractory diseases. The literature review revealed few large, controlled studies that compared efficacy of adjunctive antibiotic use to mechanical therapy alone. Even fewer studies evaluated the efficacy of one antibiotic relative to another. However, based on the evidence available, certain conclusions were drawn. Adjunctive use of an antibiotic along with mechanical debridement is recommended for the treatment of Actinobacillus actinomycetemcomitans-associated periodontitis as an acceptable therapeutic regimen. Due to the emergence of tetracycline-resistant A. actinomycetemcomitans, the combination of metronidazole and amoxicillin may be preferable. In aggressive refractory periodontitis, compelling evidence exists that the use of an appropriate adjunctive antibiotic frequently gives a more favorable clinical response than mechanical therapy alone. Unfortunately, the selection of antibiotic is not as clear and is probably case-dependent. Positive responses have been reported with amoxicillin/clavulanic acid, clindamycin, metronidazole, and the combination therapy metronidazole plus amoxicillin. The introduction of local delivery antibiotics specifically for the treatment of periodontitis offers a novel concept for the treatment of localized disease. The latter, in particular, may prove useful in the treatment of recurrent disease activity or where only a few individual sites are involved.