Acne vulgaris is an extremely common disorder affecting many adolescents and adults throughout their lifetimes. The pathogenesis of acne is multifactorial and is thought to involve excess sebum, follicular hyperkeratinization, bacterial colonization, and inflammation. Many therapeutic options exist for treating acne, including topical benzoyl peroxide, topical and oral antibiotics, topical and oral retinoids, and oral contraceptives. Oral antibiotics have been a mainstay in the treatment of acne for decades and function by exerting an antibacterial effect by reducing the follicular colonization of Propionibacterium acnes. Systemic antibiotics also have anti-inflammatory and immunomodulatory properties. This article reviews the English language literature on the efficacy of various systemic antibiotics for treating acne vulgaris, including second-line and less historically used medications. We discuss the tetracyclines, including subantimicrobial dose doxycycline, macrolides (notably azithromycin), trimethoprim-sulfamethoxazole, cephalosporins, and fluoroquinolones as treatment options for acne vulgaris.