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Despite considerable evidence that cytoplasmic microtubules play some role in guiding or controlling the locomotion of tissue cells, the nature of this control is not understood. In particular, little is known about the role of microtubules in the exertion of propulsive ‘traction’ forces, or about microtubule effects on the organization of the cytoplasmic actin stress fibers. In this study, the silicone rubber substratum technique was used in combination with fluorescence microscopy in order to observe the effects of microtubule-depolymerizing drugs on the contractile strength and organization of cytoplasmic actin networks. Perfusion with a variety of microtubule poisons (either colcemid, nocodazole or vinblastine) was found to cause a rapid and substantial strengthening of fibroblast contractility. This was demonstrated in two established fibroblast cell lines, as well as in primary cultures of rat gingival fibroblasts and embryonic chick heart fibroblasts. Treatment with the drug taxol, which promotes microtubule assembly, was found to prevent the strengthening effects of the microtubule inhibitors. It was also found that the disruption of actin stress fibers by the phorbol ester tumor promoter, TPA, is reversed by microtubule poisons: stress fibers reform within 30 min of the addition of the microtubule drugs, despite the continued presence and activity of the TPA. Several possible mechanisms are considered, including the idea that microtubule assembly normally exerts a pushing force, which counterbalances part of the contractile force exerted by the actin stress fibers. However, the mechanism that seems best to account for the observations is that microtubules modulate, in an inhibitory fashion, the contractility and the state of organization of cytoplasmic actin.