Abstract The term anaphylaxis describes both immunoglobulin E (IgE) immune-mediated reactions, plus non-IgE immune-mediated, and non-allergic, non-immunologically triggered events. Comorbidities such as asthma or infection, exercise, alcohol, or stress and concurrent medications such as β-blockers and aspirin increase the risk, a concept known as ‘summation anaphylaxis’. Activated mast cells and basophils release preformed, granule-associated mediators and newly formed lipid mediators, and generate cytokines and chemokines. These cause vasodilatation, increased capillary permeability, and smooth muscle contraction, as well as attracting new cells to the area. Positive feedback enhancing mechanisms amplify the reaction in a ‘mast cell—leucocyte cytokine cascade’, although conversely reactions can be self-limiting. Parenteral penicillins, hymenopteran stings, and food are the most common causes of IgE immune-mediated fatalities, with radiocontrast media, aspirin, and other non-steroidal anti-inflammatory drugs most commonly responsible for non-IgE and non-allergic fatalities.