Publisher Summary Many biologically active molecules convey their signals via receptors coupled to heterotrimeric guanine nucleotide binding proteins (G proteins). Molecular cloning has resulted in the identification of 16 distinct Gα subunits, which are commonly divided into four families based on their sequence similarity. On activation, G-protein-coupled receptors (GPCRs) interact with their cognate heterotrimeric G protein, inducing GDP release with subsequent GTP binding to the α subunit. The exchange of GDP for GTP leads to dissociation of the Gβγ dimer from the Got subunit, and both initiate unique intracellular signaling responses. In all G proteins studied GTP is bound as a complex with Mg2+, and the GTP- and Mg2+-binding sites are tightly coupled. Dominant negative constructs of the Gα subunit have been made in which mutations are introduced at residues known to contact the magnesium ion. This chapter shows that the carboxyl termini from various G protein α subunits are important sites of receptor binding, and peptides corresponding to the carboxyl terminus can be used as competitive inhibitors of receptor-G protein interactions.