Although it is generally accepted that tubulin plays an important role in G-protein-mediated signal transduction in a variety of systems, the mechanism of this phenomenon is not completely understood. G-protein-tubulin interaction at the cell membrane and the cytosol, and the influence of such an interaction on cellular signaling are discussed in this review article. Because the diameter of a microtubule is 25 nm and the plasma membrane is 9-11 nm thick, it is not possible for membrane-associated tubulin to assemble into a complete microtubule in the membrane environment. However, tubulin heterodimers may be able to function in the membrane environment as individual heterodimers or as polymers arranged into short protofilaments. At the cell membrane, membrane-associated tubulin may influence hormone-receptor interaction, receptor-G-protein coupling, and G-protein-effector coupling. Structural proteins, such as tubulin, can participate in cellular signaling by communicating through physical forces. By virtue of its interaction with the submembranous network of cytoskeletal proteins, tubulin, when perturbed in one locus, can transmit large changes in conformations to other points. Thus, GTP binding to membrane-associated tubulin might lead to a conformational change in either receptors or G proteins. This may, in turn, influence the binding of an agonist to its receptor. On the other hand, in the cell cytosol, subsequent to agonist-induced translocation of G-proteins from the membrane compartment to the cytosol, G-proteins may affect microtubule formation. In GH3 and AtT-20 cells (stably expressing TRH receptor), transiently transfected with Gq alpha cDNA, soluble tubulin levels decreased in Gq alpha-transfected GH3 and AtT-20 cells, by 33% and 52%, respectively. These results suggest that G-proteins may have a direct effect on the microtubule function in vivo. Because tubulin and G-protein families are ubiquitous and highly conserved, an interaction between these two protein families may occur in vivo, and this, in turn, can have an impact on signal transduction. However, the physiological significance of this interaction remains to be demonstrated.