Mas-related gene X2 (MrgX2) is a receptor expressed on human mast cells (MCs) but its role in health and disease is unknown. We therefore utilized immunohistochemistry and immunofluorescence techniques to determine the expression of MrgX2 in normal and diseased human tissue. We also tested the feasibility of utilizing humanized mice as a model for in vivo functional studies on MrgX2. We analyzed control samples as well as skin, gingiva and lung samples from patients with atopic dermatitis, rosacea, chronic periodontitis and asthma and found that MCs in healthy and diseased skin, gingiva and lungs express MrgX2. The expression of MrgX2 was not significantly different in atopic dermatitis, rosacea and chronic periodontitis compared with controls. However, in rosacea, there was a significant reduction in tryptase expression by MCs suggestive of increased degranulation. There was a significant increase in MCs, MrgX2-positive cells as well as MrgX2-positive MCs in asthmatic lung tissue compared with healthy lung tissue. Finally, we found that human MCs, which develop in the lungs of humanized mice, express MrgX2. Therefore, expression of MrgX2 by MCs in healthy skin, gingiva and lung suggests that it plays an important role in host defense. Our finding that MCs that express MrgX2 are upregulated in chronic asthma suggests it participates in the pathogenesis of asthma. Humanized mice may be used as models for future in vivo studies on the role of MrgX2 in human disease conditions.