Non-immunologic, IgE-independent mast cell (MC) activation induced by certain drugs and neuropeptides (such as substance P) has been shown to be mediated by the recently identified G protein-coupled receptor MRGPRX2 (MrgX2) found almost exclusively on connective tissue MC. Also, MrgX2 expression was found to be significantly upregulated on human skin MC of patients with chronic urticaria {1}. The mouse analogue of this receptor is Mrgprb2, however, only a few drugs known to cause adverse reactions (ADR) in humans have been shown to evoke a similar response in mice. This is because the binding affinity of the Mrgprb2 receptor analogue on mice MC for the specific drugs causing ADR is much lower than that of the MrgX2 receptor on human MC. This species-specific disparity in binding affinity has severely hampered the ability to study the underlying mechanisms of ADR and to develop therapeutic strategies. To overcome this obstacle, the authors generated humanized mice that exhibited high human MC numbers in various tissues that also expressed the human MrgX2 receptor, mainly in the skin. Of note, large numbers of MrgX2-expressing human MC could be cultured from the bone marrow (BM) of these humanized mice, enabling these mice to be an important source of human MC for in vitro studies of MrgX2-related MC activities. Indeed, BM-derived cultured MC from these humanized mice exhibited enhanced degranulation on exposure to substance P or compound 48/80, as well as to drugs (radiocontrast media) known to provoke serious non-immune allergic reactions in various subjects. Furthermore, passive cutaneous anaphylaxis could be elicited in these mice on exposure to the contrast media. In conclusion, these humanized MrgX2-expressing mice may serve as a powerful platform for both in vitro and in vivo studies of non-immunologic human MC activation and allergic responses due to various drugs such as radiocontrast media, NSAIDs, opiates, vancomycin, icatiband, and ciprofloxacin. This experimental model system may also serve as a useful tool for developing therapeutic approaches for these MC-mediated inflammatory responses, as well as for screening novel drugs for their adverse reaction causing potential.