Several different risk factors and conditions may predispose to severe life-threatening anaphylaxis. Systemic mastocytosis (SM) is one such condition. Although many SM patients are suffering from mild or even no mediator-related symptoms, others have recurrent episodes of severe anaphylaxis, with clear signs of a mast cell activation syndrome (MCAS) despite prophylactic therapy with anti-mediator-type drugs. In several of these patients, an IgE-dependent allergy is diagnosed. The severity and frequency of MCAS reactions neither correlate with the burden of neoplastic mast cells nor with the levels of specific IgE or the basal tryptase level. However, there is a relationship between severe anaphylaxis in SM and the type of allergen. Notably, many of these patients suffer from hymenoptera venom allergy. Currently recommended therapies include the prophylactic use of anti-mediator-type drugs, long-term immunotherapy for hymenoptera venom allergic patients, and epinephrine-self-injector treatment for emergency situations. In patients who present with an excess burden of mast cells, such as smouldering SM, cytoreductive therapy with cladribine (2CdA) may reduce the frequency of severe events. For the future, additional treatment options, such as IgE-depletion or the use of tyrosine kinase inhibitors blocking IgE-dependent mediator secretion as well as KIT activation, may be useful alternatives.