Mast cells possess an array of potent inflammatory mediators capable of inducing acute symptoms after cell activation, including urticaria, angioedema, bronchoconstriction, diarrhea, vomiting, hypotension, cardiovascular collapse, and death in few minutes. In contrast, mast cells can provide an array of beneficial mediators in the setting of acute infections, cardiovascular diseases, and cancer. The balance between the detrimental and beneficial roles of mast cells is not completely understood. Although the symptoms of acute mast cell mediator release can be reversed with epinephrine, adrenergic agonists, and mediator blockers, the continued release of histamine, proteases, prostaglandins, leukotrienes, cytokines, and chemokines leads to chronic and debilitating disease, such as mastocytosis. Identification of the molecular factors and mechanisms that control the synthesis and release of mast cell mediators should benefit all patients with mast cell activation syndromes and mastocytosis.