A direct interaction between tubulin and several pro-apoptotic and anti-apoptotic members of the Bcl-2 family has been demonstrated by effects oil the assembly of microtubules from pure rat brain tubulin. Bcl-2, Bid, and Bad inhibit assembly sub-stoichiometrically, whereas peptides from Bak and Bax promote tubulin polymerization at near stoichiometric concentrations. These opposite effects oil microtubule assembly are mutually antagonistic. The BH3 homology domains, common to all members of the family, are involved in the interaction with tubulin but do not themselves affect polymerization. Pelleting experiments with paclitaxel-stabilized microtubules show that Bak is associated with the microtubule pellet, whereas Bid remains primarily With the unpolymerized fraction. These interactions require the presence of the anionic C-termini of alpha- and beta-tubulin as they do not occur With tubulin S in which the C-termini have been removed. While in no way ruling Out other pathways, such direct associations are the simplest potential regulatory mechanism for apoptosis resulting from disturbances in microtubule or tubulin function. Published by Elsevier Inc.