The primary indication for systemic antibiotics is acute therapy for moderate-to-severe inflammatory acne. The preferred agents include tetracyclines and derivatives; macrolides, co-trimoxazole, and trimethoprim may represent acceptable alternatives. Antibiotics act mainly on inflammatory lesions (papules and pustules) and are only slightly comedolytic. Oral antibiotics reduce the number of Propionibacterium acnes. In addition, they have an anti-inflammatory activity. The side effects associated with oral antibiotics for acne depend on the drug; however, severe side effects are not common. Resistant strains of Propionibacterium acnes to antibiotics are increasing. Thus, general guidelines are useful when utilizing oral antibiotic therapy in acne.