The pathogenesis of acne is complex and dependent on the interplay of multiple factors. Ductal epidermal hyperproliferation, excess sebum, inflammation, and the presence of P acnes all contribute to the development of acne vulgaris. Isotretinoin, arguably the most effective acne treatment, normalizes ductal hyperproliferation, greatly diminishes sebum production and sebocyte terminal differentiation, and manifests decreased numbers of P acnes organisms. Isotretinoin also exhibits anti-inflammatory properties. A positive response to isotretinoin is durable in 85% of patients after one course of therapy, despite the reversal of many of these observed changes. The exact mechanism of isotretinoin is unknown. Much remains unknown in our understanding of the pathogenesis of acne. What is the initial stimulus for follicular hyperproliferation? Why do some persons develop acne and others do not despite similar serum hormone levels and similar P acnes counts? What determines the severity of acne in a given patient? Is acne primarily an inflammatory dermatosis? Much progress has been made in the study of acne, but many questions remain. Perhaps the most important question is, how do we treat our patients with acne more effectively and safely than we are now? The answer to this question lies in the development of a deeper understanding of the pathogenesis of acne vulgaris.