Isotretinoin has been the most effective and long-lasting drug for the treatment of severe acne for more than 30 years and can achieve long-term remission in 70-80 % of patients after a single course. New findings concerning its influence on innate immunity, the modulation of growth factors or the time-dependent regulation of genes of inflammation or matrix metabolism contribute to an improved understanding of the dynamic mode of action of isotretinoin. The new evidence-based European S3-guideline recommends the use of Isotretinoin as a first-line medication for the treatment of severe papulopustular or conglobate acne, especially when prognostically unfavorable factors are present: family history of acne, early onset, marked seborrhea, localization on the trunk, scarring, psychosocial disability or persistent/late-type acne. The correlation of a cumulative dose of > 100-120 mg/kg with a reduced relapse rate can be regarded as established in patients with severe acne forms, whereas in milder, "off-label"-treated acne forms, a good clinical outcome can also be achieved with lower cumulative doses.