Benzoyl peroxide (BPO) is the most widely used topical acne treatment, with significant antibacterial, antikeratolytic, and comedolytic activity. It has been shown to be extremely effective as monotherapy and in combination with antibiotics or retinoids for managing comedonal and inflammatory acne lesions. As numerous clinical studies have shown, the combination of BPO plus a topical antibiotic is not only more effective but also is often better tolerated than either agent alone. Unlike antibiotics, no bacterial resistance has been noted. Adding BPO to any long-term antibiotic regimen in acne is generally recommended to help reduce populations of drug-resistant variants. Although effective combinations of BPO and antibiotics or retinoids are used, BPO monotherapy can also be extremely effective in treating mild to moderate acne with no resistance issues.