Bacterial resistance to antibiotics began to emerge soon after their introduction. Beginning in the 1970s, Propionibacterium acnes also began to show decreased sensitivity to the antibiotics typically used in acne management. Clinically, this trend has translated to decreased efficacy and even nonresponse to therapy. A variety of recommendations regarding optimum use of antibiotics in acne management have been developed to preserve the utility of these drugs. Most important is the use of combination therapy with benzoyl peroxide (BPO) to help minimize the development of resistance. Retinoids also are recommended in acne therapeutic regimens because these agents are active against most acne pathogenetic mechanisms, but they have no apparent activity preventing antibiotic resistance when used in combination with a topical antibiotic.