Propionibacterium acnes is an anaerobic bacterium that plays an important role in the pathogenesis of acne. Certain antibiotics that can inhibit P acnes colonization also have demonstrated anti-inflammatory activities in the treatment of acne, rosacea, and other noninfectious diseases. Decreased sensitivity of P acnes to antibiotics, such as erythromycin and tetracycline, has developed and may be associated with therapeutic failure. Benzoyl peroxide (BPO) is a nonantibiotic antibacterial agent that is highly effective against P acnes and for which no resistance against it has been detected to date. Retinoids are important components in combination therapy for acne, including use with antibiotics, and can serve as an alternative to these agents in maintenance therapy. By increasing our understanding of the multifaceted actions of antibiotics and the known clinical implications of antibiotic resistance, physicians can improve their decision making in prescribing these agents.