Immediate hypersensitivity reactions can pose a clinical and diagnostic challenge, mainly because of the multifarious clinical presentation and distinct underlying – frequently uncertain – mechanisms. Anaphylaxis encompasses all rapidly developing and life-threatening signs and may cause death. Evidence has accumulated that immediate hypersensitivity and anaphylaxis do not necessarily involve an allergen-specific immune response with cross-linking of specific IgE (sIgE) antibodies bound to their high-affinity IgE receptor (FcεRI) on the surface of mast cells (MCs) and basophils. Immediate hypersensitive and anaphylaxis can also result from alternative specific and nonspecific MC and basophils activation and degranulation, such as complementderived anaphylatoxins and off-target occupancy of MC and/or basophil surface receptors such as the Masrelated G protein-coupled receptor X2 (MRGPRX2). Degranulation of MCs and basophils results in the release of inflammatory mediators, which can be, depending on the underlying trigger, in a different spatiotemporal manner. In addition, hypersensitivity and anaphylaxis can occur entirely independently of MC and basophil degranulation, as observed in hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) that divert normal arachidonic acid metabolism by inhibiting the cyclooxygenase (COX)-1 isoenzyme. Finally, one should remember that anaphylaxis might be part of the phenotype of particular - sometimes poorly recognizable - conditions such as clonal MC diseases (e.g. mastocytosis) and MC activation syndrome (MCAS). This review provides a status update on the molecular mechanisms involved in both sIgE/FcεRI- and non-sIgE/FcεRIdependent immediate hypersensitivity and anaphylaxis. In conclusion, there is increasing evidence for alternative pathophysiological hypersensitivity and anaphylaxis endotypes that are phenotypically and biologically indistinguishable, which are frequently difficult to diagnose, mainly because of uncertainties associated with diagnostic tests that might not enable to unveil the underlying mechanism.