We thus propose the binding of tumor targeted IgE Fc to human MC FcεRI and subsequent triggering of this receptor upon tumor engagement mediate the anti-tumor effects of therapeutic IgE’s given the demonstrated high amounts of FcεRI on primary human MCs in the tumor milieu (157), the high numbers of FcεRI (>1 x 105/cell) that require only ≈100 receptors for full activation (67, 158), the affinity of this interaction (159), the juxtaposition of MCs with cancers cells (67), and the anti-tumor mediators released from MCs (160). The gene discussed is FCER1A; the disease is cancer.