Paradoxical reactions are defined as adverse effects that manifest as a de novo appearance or the exacerbation of a condition that commonly responds to a certain class of drug. A well-known example of paradoxical reaction is the debut of psoriatic eruptions when patients undergo anti-tumor necrosis factor-alpha (TNF-α) therapy for inflammatory bowel disease. Initially, they were described as isolated events among patients who received the aforementioned drug agents for inflammatory rheumatic diseases. Later, paradoxical reactions have been reported in association with other conditions as psoriasis and inflammatory bowel disease and different biologic drugs or classes. Furthermore, paradoxical reactions have been reported with other biologics than TNF-α inhibitors, such as ustekinumab and IL-17 and IL-23 inhibitors. Sometimes, differentiating a true paradoxical reaction from a disease flare caused by efficacy loss can be challenging. The hypothesis concerning its pathophysiology consists in an imbalance of the immunity and inflammatory mechanisms and cells implied (cytokines, lym-phocytes…). These reactions may hinder proper patient management and result in catastrophic consequences. Thus, close surveillance and early recognition of these drug class effects is crucial.