AG-30/5C is an angiogenic host defense peptide (HDP) that activates human mast cells (MC) via an unknown mechanism. Using shRNA-silenced human MC line (LAD2) and stably transfected RBL-2H3 cells, we demonstrate that AG-30/5C induces MC degranulation via Mas-related G protein coupled receptor (GPCR) X2 (MRGPRX2). Most GPCRs signal via parallel and independent pathways mediated by G proteins and β-arrestins. AG-30/5C and compound 48/80 induced similar maximal MC degranulation via MRGPRX2, which was abolished by pertussis toxin (PTx). However, compound 48/80 induced a robust β-arrestin activation as determined by transcriptional activation following arrestin translocation (Tango) but AG-30/5C did not. Overnight culture of MCs with compound 48/80 resulted in reduced cell surface MRGPRX2 expression and this was associated with a significant decrease in subsequent MC degranulation in response to compound 48/80 or AG-30/5C. However, AG-30/5C pretreatment had no effect on cell surface MRGPRX2 expression or degranulation in response to compound 48/80 or AG-30/5C. Icatibant, a bradykinin B 2 receptor antagonist, promotes MC degranulation via MRPGRX2 and causes pseudo-allergic drug reaction. Icatibant caused MC degranulation via a PTx-sensitive G-protein but did not activate β-arrestin. A screen of the NIH Clinical Collection library (NCC-1) led to the identification of resveratrol as an inhibitor of MRGPRX2. Resveratrol inhibited compound 48/80-induced Tango and MC degranulation in response to compound 48/80, AG-30/5C and Icatibant. This study demonstrates the novel finding that AG-30/5C and Icatibant serve as G-protein biased agonists for MRGPRX2, but compound 48/80 signals via both G protein and β-arrestin with distinct differences in receptor regulation.