Purpose of Review <p>Systemic mastocytosis and mast cell activation syndromes rely on serum and urine mediators and mediator metabolites for diagnosis. Mast cells produce many mediators but only several have diagnostic utility. This review covers the physiology and diagnostic utility of mast cell mediators in clonal and nonclonal mast cell activation disorders.</p> Recent Findings <p>Mast cell mediators and mediator metabolites are released during mast cell activation. Measurement of mediators is useful in both clonal and nonclonal mast cell activation disorders.</p> Summary <p>An understanding of the utility and clinical situations in which mast cell mediators change management in important and incorporating mast cell mediators into diagnostic algorithms may improve diagnosis and treatment.</p>