Colchicine and nocadazole both depolymerize microtubules in cultured fibroblasts and lead to a rapid inhibition of tubulin synthesis. The level of translatable tubulin mRNA is greatly reduced in drug-treated cells as demonstrated by translation in a reticulocyte-derived in vitro protein synthesizing system. A model of tubulin synthesis regulation is proposed in which the elevated level of unpolymerized tubulin in drug-treated cells inhibits the formation of new tubulin mRNA and the preexisting message decays rapidly. In agreement with this model, tubulin message is found to be short-lived and has an approximately 2 hr half-life in cells treated with actinomycin D. Another prediction of the proposed model is that destabilization of microtubules without a concomitant increase in free tubulin will not inhibit tubulin synthesis. Vinblastine also disrupts microtubules but leads to the aggregation of tubulin into large paracrystals with an apparent decrease in the concentration of free tubulin. This drug does not inhibit tubulin production but rather leads to a measurable enhancement of tubulin synthesis.