Although mast cells are emerging as key negative regulators in certain settings of inflammation, their notoriety as efficient pro-inflammatory effector cells is primarily underscored by the ability to provoke strong immunoglobulin E (IgE)-mediated responses to allergens in sensitized individuals. Whether in the skin, lung or gut, cross-linkage of the high affinity IgE receptor (FcRI) by antigen ligation on the surface of MCs stimulates the release of inflammatory mediators that can drive the allergic response. Restraint of intracellular signal transduction pathways that propagate MC-derived pro-inflammatory mediator release is necessary to limit activation and restore homeostasis. We have found that a novel E3 ubiquitin ligase, which has not previously been identified to regulate the IgE-FcRI signalsome in mast cells, is required to optimally limit the intensity and duration of positive signal transduction. Dysregulation of this process results in a striking exacerbation of the cutaneous reactions associated with IgE-induced anaphylaxis in vivo. Thus, our findings shed new light on the inherent molecular mechanisms that tightly regulate the intricate signalsome following IgE-mediated activation in mast cells.