The discovery of Mas-related G protein-coupled receptors (MRGPRs) has significantly advanced our understanding of immunity and sensory biology. This review focuses on the members of the MRGPR family expressed on immune cells and their roles in governing immune and neuro-immune pathways. MRGPRs are found on various immune cell types, including mast cells, dendritic cells, and neutrophils, and play a crucial role in controlling a wide range of immune responses, such as adverse drug reactions, inflammatory conditions, bacterial immunity, and the sensing of environmental exposures like allergens and irritants. Mast cells, which are known for their role in IgE-mediated allergic responses, can also be activated by non-IgE-dependent mechanisms, including neuropeptides like substance P (SP). The discovery that human mast cells express MRGPRX2 has led to extensive research on how this receptor drives mast cell activation. MRGPRX2 is highly expressed in connective tissue mast cells and is activated by various ligands, including cationic host-defense peptides and antimicrobial peptides. These ligands trigger mast cell degranulation and release of mediators, contributing to inflammatory responses. MRGPRs also play a role in neuroimmunology, particularly in itch and pain pathways. MRGPRX2 is involved in non-histaminergic itch, which is mediated by the release of tryptase and other pruritogens. Additionally, MRGPRX2 is implicated in pain perception, including inflammatory pain and migraine. The activation of MRGPRX2 by neuropeptides like SP and PACAP can lead to pain hypersensitivity. In dendritic cells and neutrophils, MRGPRs are expressed and regulate immune responses. For example, Mrgrpra1 is expressed in skin CD301b+ dendritic cells and promotes allergic inflammation. β-defensins secreted by keratinocytes can engage Mrgrpr2a/2b on neutrophils to enhance antibacterial responses. The structure and signaling of MRGPRs involve G-protein coupling and β-arrestin recruitment, with different MRGPRs exhibiting preferences for specific G-protein subtypes. MRGPRX2, in particular, has been targeted in clinical trials for treating skin diseases and itch conditions, such as atopic dermatitis (AD) and chronic liver and kidney diseases. Despite significant progress, several aspects of MRGPR biology remain unknown, including the mechanisms driving their restricted expression on immune cells, the functional consequences of basal activity, and the role of polymorphisms in immune cell function. Further research is needed to fully understand the immune functions of MRGPRs and to develop new therapeutics.The discovery of Mas-related G protein-coupled receptors (MRGPRs) has significantly advanced our understanding of immunity and sensory biology. This review focuses on the members of the MRGPR family expressed on immune cells and their roles in governing immune and neuro-immune pathways. MRGPRs are found on various immune cell types, including mast cells, dendritic cells, and neutrophils, and play a crucial role in controlling a wide range of immune responses, such as adverse drug reactions, inflammatory conditions, bacterial immunity, and the sensing of environmental exposures like allergens and irritants. Mast cells, which are known for their role in IgE-mediated allergic responses, can also be activated by non-IgE-dependent mechanisms, including neuropeptides like substance P (SP). The discovery that human mast cells express MRGPRX2 has led to extensive research on how this receptor drives mast cell activation. MRGPRX2 is highly expressed in connective tissue mast cells and is activated by various ligands, including cationic host-defense peptides and antimicrobial peptides. These ligands trigger mast cell degranulation and release of mediators, contributing to inflammatory responses. MRGPRs also play a role in neuroimmunology, particularly in itch and pain pathways. MRGPRX2 is involved in non-histaminergic itch, which is mediated by the release of tryptase and other pruritogens. Additionally, MRGPRX2 is implicated in pain perception, including inflammatory pain and migraine. The activation of MRGPRX2 by neuropeptides like SP and PACAP can lead to pain hypersensitivity. In dendritic cells and neutrophils, MRGPRs are expressed and regulate immune responses. For example, Mrgrpra1 is expressed in skin CD301b+ dendritic cells and promotes allergic inflammation. β-defensins secreted by keratinocytes can engage Mrgrpr2a/2b on neutrophils to enhance antibacterial responses. The structure and signaling of MRGPRs involve G-protein coupling and β-arrestin recruitment, with different MRGPRs exhibiting preferences for specific G-protein subtypes. MRGPRX2, in particular, has been targeted in clinical trials for treating skin diseases and itch conditions, such as atopic dermatitis (AD) and chronic liver and kidney diseases. Despite significant progress, several aspects of MRGPR biology remain unknown, including the mechanisms driving their restricted expression on immune cells, the functional consequences of basal activity, and the role of polymorphisms in immune cell function. Further research is needed to fully understand the immune functions of MRGPRs and to develop new therapeutics.