Topical antimicrobial agents are the first line of treatment in mild to moderate acne vulgaris. The primary pathogenic agent implicated in the development of inflammatory acne is Propionibacterium acnes. P acnes also may play a secondary role in noninflammatory acne or comedogenesis. Over the past 20 years, concern has grown about the gradual worldwide increase in the prevalence of antibiotic-resistant P acnes strains. Factors associated with the development of resistant P acnes following treatment with topical antibiotics, clinical relevance of antibiotic resistance, and strategies to reduce the incidence of P acnes resistance are discussed in this review.