Perioperative hypersensitivity reactions (POH) constitute a clinical and diagnostic challenge, a consequence of heterogeneous clinical presentations, and multiple underlying pathomechanisms. POH do not necessarily involve an allergen-specific immune response with cross-linking of specific immunoglobulin E (sIgE) antibodies on mast cells and basophils. POH can also result from alternative specific and non-specific effector cell activation/degranulation such as complement-derived anaphylatoxins and off-target occupancy of mast cell, basophil, or both surface receptors. Moreover, POH and anaphylaxis can occur independent from mast cell and basophil degranulation. The manifestations of POH primarily affect the cardiovascular, respiratory, and integumentary systems. POH present within the context of surgical or procedural pathology and the effects of surgical and anaesthetic techniques on pre-existing physiological reserve. The majority of cases of appropriately-treated intraoperative anaphylaxis can be considered a compensated cardiovascular anaphylaxis. With increasing severity of anaphylaxis, maldistribution and hypovolaemia lead to reduced venous return and circulatory failure. Treatment with a combination of epinephrine and i.v. fluid is critical for successful resuscitation, although the excessive use of epinephrine without adequate volume expansion may be deleterious. Neural control of the airways is important in the pathophysiology of bronchospasm. Anticholinergic drug premedication is beneficial in patients with hyperreactive airways. Pulmonary oedema can result from a combination of pulmonary capillary hypertension, incompetence of the alveolocapillary membrane, or both. Angioedema can be distinguished mechanistically into histaminergic and non-histaminergic (e.g. bradykinin-mediated). An understanding of the molecular mechanisms and pathophysiology of POH are essential for the immediate management and subsequent investigation of these cases.