Since its first use in dermatology last century, benzoyl peroxide (BPO) has undergone a number of reformulations, each enhancing its efficacy, tolerability, or both. Benzoyl peroxide can be used as monotherapy or in combination with oral or topical antibiotics or topical retinoids. Its antimicrobial activity is based on the generation of highly reactive oxygen radicals, a physicochemical effect to which Propionibacterium acnes has not developed resistance. In addition to its nonspecific antimicrobial activity, BPO has keratolytic, comedolytic, and anti-inflammatory activity in acne. Benzoyl peroxide can be added to antibiotic regimens to help maintain bacterial sensitivity to the antibiotic. Additive or synergistic effects of BPO-antibiotic combinations have been demonstrated. Fixed combinations of BPO with either antibiotics or a retinoid recently have become available and may improve compliance. New moisturizing vehicles and stabilized BPO formulations also have added to tolerability and convenience. Benzoyl peroxide may have underappreciated potential to treat noninflammatory acne as monotherapy or in combination with a topical retinoid, an important antibiotic-sparing strategy.