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For the treatment of moderate to severe atopic dermatitis (AD), two groups of modern systemic therapies with a total of five drugs are currently approved in Germany: biologics (dupilumab, tralokinumab) and "small molecules" (abrocitinib, baricitinib, upadacitinib). The growing armamentarium of therapy options, especially with more than one drug per substance group, makes it challenging for practitioners to select the appropriate treatment for the individual patient. In this review article, the preconditions and requirements of each drug group as well as the corresponding substances are presented comparatively. On the one hand, direct therapeutic effects on the severity of the disease are considered and, on the other hand, the spectrum of potential adverse drug reactions are discussed. In particular, short- and long-term effects, the safety profile and the patient's concomitant diseases represent key factors for shared decision-making with regard to select the optimum personalized therapy option., (© 2022. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)