Drug-induced anaphylaxis is a hyperacute reaction affecting multiple organs that can be of fatal consequence. Its incidence is increasing, consistent with a global increased sensitization to various allergens and drugs in the population. Few risk factors and mechanisms have been identified from human studies due to the rarity of anaphylactic events and their unpredictability. This systemic reaction is caused by the rapid release of a large range of functionally diverse mediators, including histamine and platelet-activating factor as the main drivers identified. Mechanisms defined from models of experimental anaphylaxis identify drug-specific antibodies of the IgE and IgG class that link the drug to antibody receptors on multiple cell types, causing their activation and mediator release. In the case of drugs with peculiar chemical structures, antibodies may not be necessary because drug-binding receptors, such as Mas-related G protein-coupled receptor member X2, have been identified. This review describes the complex reaction leading to drug-induced anaphylaxis that can involve various antibody classes, various cell types-including mast cells, neutrophils, platelets, basophils, macrophages, and monocytes-and their mediators and receptors that, importantly, can be activated alone or in association to participate in the severity of the reaction.