This review summarizes current information regarding the use of antimicrobial agents for the treatment of patients with inflammatory acne. A number of drugs have been used effectively as topical or systemic therapy, often in combination with benzoyl peroxide or a retinoid. Propionibacterium acnes exhibits high in vitro sensitivity to a wide range of antimicrobials, including ampicillin, clindamycin, erythromycin, tetracycline, doxycycline, nadifloxacin, ofloxacin, minocycline, cephalexin, and gentamycin. However, not all of these drugs are equally effective in penetrating the lipid-filled microcomedo and reducing numbers of P. acnes in the skin. Antimicrobial therapy, particularly systemic treatment, may be complicated by the potential for drug-drug interactions. Historically, the potential for antimicrobials to reduce the effectiveness of oral contraceptives has been a concern in the treatment of acne. However, there is evidence to suggest that such an interaction does not take place in patients being treated with the antimicrobials most often used in dermatological practice. Antimicrobial therapy for acne has also been complicated by the emergence of antibiotic-resistant strains of P. acnes. Increasing P. acnes resistance can be combated by judicious use of retinoids in combination with antibiotics to reduce inflammation and infection, and employment of retinoids for maintenance therapy.