MRGPRX2, a novel G -coupled human mast cell receptor, mediates non-immune adverse reactions without the involvement of antibody priming. Constitutively expressed by human skin mast cells, MRGPRX2 modulates cell degranulation producing pseudoallergies manifesting as itch, inflammation, and pain. The term pseudoallergy is defined in relation to adverse drug reactions in general and immune/non-immune-mediated reactions in particular. A list of drugs with MRGPRX2 activity is presented including a detailed examination of three important and widely used approved therapies, neuromuscular blockers, quinolones, and opioids. For the clinician, the significance of MRGPRX2 is considered as an aid in distinguishing and ultimately identifying specific immune and non-immune inflammatory reactions. Anaphylactoid/anaphylactic reactions, neurogenic inflammation, and inflammatory diseases with a clear or strongly suspected association with MRGPRX2 activation are examined. Inflammatory diseases include chronic urticaria, rosacea, atopic dermatitis, allergic contact dermatitis, mastocytosis, allergic asthma, ulcerative colitis, and rheumatoid arthritis. MRGPRX2- and allergic IgE/FcεRI-mediated reactions may be clinically similar. Importantly, the usual testing procedures do not distinguish the two mechanisms. Currently, identification of MRGPRX2 activation and diagnosis of pseudoallergic reactions is generally viewed as a process of exclusion once other non-immune and immune processes, particularly IgE/FcεRI-mediated degranulation of mast cells, are ruled out. This does not take into account that MRGPRX2 signals via β-arrestin which can be utilized to detect MRGPRX2 activation by employing MRGPRX2 transfected cells to assess MRGPRX2 activation via two pathways, the G-protein-independent β-arrestin pathway and G-protein-dependent Ca pathway. Testing procedures, interpretations for distinguishing mechanisms, patient diagnosis, agonist identification, and drug safety evaluations are addressed.