Mast cells are strategically distributed as sentinels, which alert the immune system upon infiltration of foreign materials and pathogens. Mast cells trigger inflammatory responses by releasing their pro-inflammatory mediators. Some materials are recognized by IgE and cross-link the FceRI and others directly activate surface membrane receptors expressed in mast cells. Although it long remained to be clarified how mast cells are activated in the latter cases, a series of recent studies have revealed that Mas-related G protein-coupled receptors (Mrgprs) should play critical roles in IgE-independent degranulation of mast cells. On the other hand, large-scale ligand screenings suggested that an orphan G protein-coupled receptor (GPCR), GPR35, should be the candidate for the target molecules of mast cell stabilizers, such as disodium cromoglycate. Here I present our recent progress in the investigation of the roles of various Mrgpr family receptors and GPR35 expressed in murine mast cells. Development of the antagonists of Mrgprs and the agonists of GPR35 might open up novel therapeutic approaches for inflammatory diseases, in which tissue mast cells play a primary role.