Our understanding of IgE-mediated drug allergy relies on the hapten concept, which is well established in inducing reactions of the immune system to small molecules like drugs. The role of hapten-carrier adducts in re-challenge reactions leading to mast cell degranulation and anaphylaxis is unclear. Based on clinical observations, the speed of adduct formation, skin and in-vitro tests to inert drug molecules, a different explanation of IgE-mediated reactions to drugs is proposed: These are a) A natural role of reduced mast cell (MC) reactivity in developing IgE-mediated reactions to drugs. This MC-unresponsiveness is antigen-specific and covers the serum drug concentrations, but allows reactivity to locally higher concentrations. b) Some non-covalent drug-protein complexes rely on rather affine bindings and have a similar appearance as covalent hapten-carrier adducts. Such drug-protein complexes represent so-called “fake antigens”, as they are unable to induce immunity, but may react with and crosslink preformed drug-specific IgE. As they are formed very rapidly and in high concentrations, they may cause fulminant MC degranulation and anaphylaxis. c) The generation of covalent hapten-protein adducts requires hours, either because the formation of covalent bonds requires time or because first a metabolic step for forming a reactive metabolite is required. This slow process of stable adduct formation has the advantage that it may give time to desensitize mast cells, even in already sensitized individuals. The consequences of this new interpretation of IgE mediated reactions to drugs are potentially wide-reaching for IgE-mediated drug allergy but also allergy in general.