A significant number of patients with moderate-to-severe inflammatory acne are candidates for oral antibiotic therapy. Use of tetracycline for acne has yielded to second-generation molecules doxycycline and minocycline, which are associated with numerous benefits over their predecessor, especially less frequent dosing and improved safety. Nonetheless, these agents are associated with certain potential side effects, including gastrointestinal (GI) concerns, staining of developing teeth in children, candidiasis, vestibular concerns and, somewhat more controversially, photosensitivity. Additionally, minocycline may be associated with the development of autoantibodies, including anti-nuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA) and anti-phospholipid antibodies with or without associated clinical symptoms. Given their similar efficacy for the management of moderate-to-severe acne vulgaris, the choice of doxycycline or minocycline may depend on specific clinical considerations, including patient satisfaction with therapy, compliance and convenience. Data and clinical experience suggest that enteric-coated doxycycline, with its low rate of GI symptoms, may represent a more tolerable treatment option for many acne patients and therefore be associated with better likelihood of compliance.