Mast cell activation (MCA) occurs in a number of different clinical conditions, including IgE-dependent allergies, other inflammatory reactions, and mastocytosis. MCA-related symptoms may be mild, moderate, severe, or even life-threatening. The severity of MCA depends on a number of different factors, including genetic predisposition, the number and releasability of mast cells involved in the reaction, the type of allergen, presence of specific IgE, and presence of certain comorbidities. In severe reactions, MCA can be documented by a substantial increase in the serum tryptase level above baseline. When symptoms are recurrent, are accompanied by an increase in mast cell–derived mediators in biological fluids, and are responsive to treatment with mast cell–stabilizing or mediator-targeting drugs, the diagnosis of mast cell activation syndrome (MCAS) is appropriate. Based on the underlying condition, these patients can further be classified into i) primary MCAS where KIT-mutated, clonal mast cells are detected, ii) secondary MCAS where an underlying inflammatory disease, often in the form of an IgE-dependent allergy, but no KIT-mutated mast cells, is found, and iii) idiopathic MCAS, where neither an allergy or other underlying disease, nor KIT-mutated mast cells are detectable. It is important to note that in many patients with MCAS, several different factors act together to lead to severe or even life-threatening anaphylaxis. Detailed knowledge about the pathogenesis and complexity of MCAS, and thus establishing the exact final diagnosis, may greatly help in the management and therapy of these patients.