Interferon (IFN)-gamma is considered a key cytokine of innate and adaptive immunity playing pivotal roles in host defence against microbial pathogens and tumours, and exerts profound antiproliferative and antifibrotic effects. In this review we discuss applications and perspectives of IFN-gamma in clinical dermatology, such as papillomavirus and bacterial infections, tumours, atopic dermatitis, and fibrotic conditions such as scleroderma and postradiation fibrosis. Moreover, we give a summary of the pharmacologic properties including main side effects and potential risk factors of IFN-gamma therapy. Although former enthusiasm for IFN-gamma (e.g. in atopic dermatitis) has subsided, this cytokine might remain a promising tool (and target) in clinical dermatology, due to its central immunobiologic functions, better characterization of its kinetics in diseases facilitating optimized treatment schedules, and successful applications in fibrotic conditions such as scleroderma, idiopathic pulmonary and skin postradiation fibrosis.