The recent discovery that the orphan GPCR MRGPRX2 likely plays a crucial role in mast cell activation has opened up new avenues.19,53 Specifically, MRGPRX2 may be key for modulating and eventually treating non-IgE-dependent hypersensitivities.19 These include urticaria,23 rosacea,29 and atopic dermatitis,36 but also allergic reactions against many drugs, all of which lack efficient treatment options.19 Moreover, various inflammatory diseases, including chronic inflammation and fibrosis, e.g., asthma and lung fibrosis,31 may benefit from treatment with MRGPRX2 antagonists. The gene discussed is MRGPRX2; the disease is urticaria.