The application of biologics such as monoclonal antibodies for targeted therapy may lead to immediate adverse drug reactions with different pathophysiological mechanisms. Some of them are due to the immunogenicity of these drugs and are truly allergic, some of them are non-allergic, some are on-target, and some are off-target. The main example of non-allergic reactions are infusion reactions, mainly induced by cytokine release. They generally occur already at the first application and symptoms may decrease in subsequent applications. Allergic reactions need a preceding sensitization phase and therefore may not occur at first application. However, if the IgE-mediated reaction is due to cross-reactivity, they may occur at the first application of the monoclonal antibody. The management of these reactions depends on their severity and the ultimate need to treat the patient with these drugs.