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Heterotrimeric guanine nucleotide binding proteins (G proteins) have a crucial role as molecular switches in multiple G protein-coupled receptors (GPCRs) signaling pathways via regulation of downstream effector molecules such as phospholipase C and adenylyl cyclase.According to structural and functional similarities of α-subunits, G proteins are divided into four subfamilies; Gαs, Gαi/o, Gαq/11, and Gα1 2/13, and the most α-as well as βγ-subunits are abundantly expressed on immune cells.G proteins are now recognized as important immunomodulatory factors, which regulate many immune system cellular functions, including cell migration, activation, survival, proliferation, differentiation and cytokine secretion.In this review, we cover recent findings on the roles of subforms of G proteins, with a focus on their regulation of the pathways involved in the immune function and autoimmune diseases.