Gz is the only pertussis-toxin-insensitive member of the inhibitory G protein subfamily. The unique pattern of tissue distribution of Gz suggests it may carry out tissue-specific functions, albeit it appears to share the same profile of G-protein-coupled receptors with Gi. The knowledge of the structural elements of alpha z for receptor coupling and specificity has been enriched by constructing chimeric molecules. Biochemical characteristics of alpha z are considerably different from other G protein alpha-subunits. The regulation of the GTP hydrolysis activity of alpha z by various GTPase-activating proteins and the functional impact of the PKC-mediated phosphorylation of alpha z are discussed. Different routes of signaling pathways that Gz could engage in have been explored. Furthermore, the possible involvement of Gz in retrograde axonal transport and various immune responses shed lights in understanding the physiological importance of Gz.