We developed a robust and reproducible MC-based assay to improve the diagnosis of IgE-mediated allergy using human MCs derived from human progenitor cells. hMCs sensitized with sera from patients with peanut, grass pollen, and Hymenoptera (wasp venom) allergy demonstrated allergen-specific and dose-dependent degranulation by using both expression of surface activation markers (CD63 and CD107a) and functional assays (PGD2 and β-hexosaminidase release). The gene discussed is CD63; the disease is Allergy.