Microtubule-perturbing drugs have become front-line chemotherapeutics, inducing cell-cycle crisis as a major mechanism of action. However, these agents show pleiotropic effects on cells and can induce apoptosis through other means. Paclitaxel, a microtubule-stabilizing agent, induces a caspase-dependent apoptosis, although the precise mechanism(s) remain unclear. Here, we used genetic approaches to evaluate the role of caspase 8 in paclitaxel-mediated apoptosis. We observed that caspase 8-expressing cells are more sensitive to paclitaxel than caspase 8-deficient cells. Mechanistically, caspase 8 was found associated with microtubules, and this interaction increased after paclitaxel treatment. The prodomains death effector domains (DEDs) of caspase 8 were sufficient for interaction with microtubules, but the caspase 8 holoprotein was required for apoptosis. DED-only forms of caspase 8 were found in both primary and tumor cell lines, associating with perinuclear microtubules and the centrosome. Microtubule association, and paclitaxel sensitivity, depends on a critical lysine (K156) within a microtubule-binding motif (KLD) in DED-b of caspase 8. The results show an unexpected pathway of apoptosis mediated by caspase 8.