Biologic drugs, which are molecules designed to act on specific immune system targets, have been shown to be very effective in treating various dermatological, rheumatological, and systemic diseases. As a group, they have an acceptable safety profile, but their use has been associated with the onset of both systemic and organ-specific inflammatory conditions. True paradoxical reactions are immune-mediated disorders that would usually respond to the biologic agent that causes them. There is still debate about whether certain other adverse reactions can be said to be paradoxical. The hypotheses proposed to explain the pathogenesis of such reactions include an imbalance in cytokine production, with an overproduction of IFN-α and altered lymphocyte recruitment and migration (mediated in part by CXCR3), and the production of autoantibodies. Some biologic therapies favor granulomatous reactions. While most of the paradoxical reactions reported have been associated with the use of TNF-α inhibitors, cases associated with more recently introduced biologic therapies -such as ustekinumab, secukinumab, and ixekizumab- are increasingly common. The study of paradoxical adverse events not only favors better management of these reactions in patients receiving biologic therapy, but also improves our knowledge of the pathogenesis of chronic inflammatory diseases and helps to identify potential therapeutic targets.