Summary Isotretinoin (13-cis retinoic acid) is the most potent known inhibitor of sebum production. The multiple modes of action for isotretinoin, including suppression of sebaceous gland activity, normalization of the pattern of keratinization within the sebaceous gland follicle, inhibition of inflammation, reduction of growth of Propionibacterium acnes in a secondary manner and, as currently shown, normalization of the expression of matrix tissue metalloproteinases and their inhibitors make this compound the single most effective in the treatment of severe recalcitrant nodulocystic acne, and in the prevention of acne scarring. Several generic formulations for oral use have recently been introduced, in addition to the brand formulations Roaccutane and Accutane (Roche). This development, considering the high risk of teratogenicity associated with oral isotretinoin use, has led the European Commission and the European Medicines Agency (EMEA) to release a directive towards the harmonization of the Summary of Product Characteristics (SPC). This has similarities to US FDA regulations, a matter that caused the reaction of the Forum for the Improvement of Clinical Trials in Acne. Physician's experience, coupled with proper patient selection, dose adjustment or discontinuation of treatment, and routine monitoring for potential toxicity, has allowed the successful prevention and management of most adverse effects associated with isotretinoin.