Acne has adverse emotional consequences and profound negative effects on psychosocial functioning that have been associated with increased rates of depression, anxiety, suicidal ideation, and suicidal attempts. Both the classic and modern features underlying acne pathogenesis include disturbed sebaceous gland activity with seborrhea and alterations of the quality of sebum lipids, dysregulation of the hormone microenvironment, and follicular hyperkeratinization. The multifactorial pathogenesis of acne indicates that combination therapies are more likely to be of increased benefit than single-treatment regimens, with the exception of systemic isotretinoin. In inflammatory acne, the concomitant use of a topical retinoid with other topical or systemic antibiotics can enhance the beneficial effect. Isotretinoin has revolutionized the management of severe and/or recalcitrant acne, being the only drug available that affects all major pathogenic factors. Pharmacokinetic studies have shown that absorption can be doubled by taking isotretinoin with or after a meal compared with the fasting state.