Introduction: The recent significant breakthroughs in the understanding of the pathogenetic mechanisms of psoriasis and other immune-mediated inflammatory disorders, have led to the emergence of a wide array of biologic agents or biologics, which are especially designed to target selective intracellular or extracellular components and pathways of the dysregulated immune response.Method: These targeted biologic agents have altered the landscape in dermatotherapy aiming to offer higher therapeutic efficacy and an alternative in patients who either failed on conventional systemic regimens or have no other therapeutic options. In the last two decades, the number of the commercially available biologic agents and the extent of their use have dramatically increased; today, these compounds represent a substantial part of modern dermatologic armamentarium. Results: Due to the immunosuppressive potential of biologics, serious concerns were raised about their safety profile, already during the pre-approval period. These concerns did not subside after the incorporation of the postmarketing experience, particularly after the withdrawal of a biologic agent (efalizumab) due to its serious and even fatal side effects. Conclusion: The purpose of the present article is to review the cutaneous and systemic side effects of all systemic biologic agents used so far in modern treatment of non-malignant skin disorders and to contribute to a better and updated awareness of their safety risks among clinicians, which will enable the latter to make the best informed and personalized drug selection and therapeutic decisions. This review was mainly based on data derived from Medline and Scopus databases and from manufacturing companies, as well.