In normal humans, tryptase, a serine protease with multiple biological activities, is synthesized nearly exclusively by mast cells (MCs). While immature forms of tryptase (␣-and ␤monomers) are constantly released by MCs and can be measured in the serum of normal individuals as the basal serum tryptase (BST) level, mature tryptases (mostly tetramers of ␤-tryptase) are retained in the secretory granules of MCs and are released only upon cell activation. Such MC activation occurs during IgE-mediated allergic reactions and increased levels of tryptase, which can be measured immediately after degranulation, are involved in the pathophysiology of immediate hypersensitivity. Interestingly, recent studies have reported that around 5% of the general population present with a genetic trait called hereditary alpha-tryptasemia (H␣T). In H␣T+ patients, the BST level is increased. Mastocytosis are a group of hematologic neoplasms characterized by an accumulation of atypical MCs in one or several organs/tissues, often accompanied by MC activation. Increased BST level is a hallmark of systemic mastocytosis (SM) and a diagnostic, prognostic and follow-up marker. Interestingly, the incidence of the H␣T trait has been found increased in SM patients (up to 18% of the cases) and H␣T+ SM patients are more prone to develop anaphylaxis, making H␣T a disease penetrance and phenotype modifier.