In this review, we will firstly outline the characteristics and downstream signaling of MRGPRX2, a very unique GPCR without parallel, and secondly discuss how MRGPRX2 activation may contribute to the etiology of neurogenic inflammation and pain, type 2 inflammatory reactions such as atopic dermatitis (AD), chronic urticaria (CU), allergic contact dermatitis (ACD), non-histaminergic itch, and small molecule compound-induced pseudoallergy. Here, MRGPRX2 is linked to Alzheimer disease.