Azithromycin is a macrolide antibiotic used extensively in medicine for the treatment of a wide range of infections such as upper respiratory tract infections, middle ear infections, sexually transmitted infections and trachoma. It is also effective against the most common periodontopathogens. The versatility of the macrolides extends beyond their antibiotic properties as a result of their well-documented immune-modulating/anti-inflammatory effects. Macrolides, including azithromycin, are therefore used to treat diseases not associated with bacteria, such as severe asthma, chronic obstructive pulmonary diseases and, more recently, cystic fibrosis. Azithromycin is concentrated in neutrophils, macrophages and particularly fibroblasts; all of these cells are central players in the pathogenesis of most periodontal diseases. This paper reviews the diverse properties of azithromycin and the clinical periodontal studies of its effects in both the treatment of periodontitis and in resolving drug-related gingival overgrowth. Evidence exists to support the use of a single course of azithromycin in the treatment of advanced periodontal diseases. Azithromycin could have a triple role in the treatment and resolution of periodontal diseases: suppressing periodontopathogens, anti-inflammatory activity and healing through persistence at low levels in macrophages and fibroblasts in periodontal tissues, even after a single course of three tablets. If future periodontal research confirms these properties, it could become a valuable host-modulator in periodontal treatment.