Past studies have shown that melanoma cells have largely adapted to endoplasmic reticulum (ER) stress. In this study we report that melanoma cells under ER stress are more resistant to apoptosis induced by the microtubule-targeting chemotherapeutic drugs, docetaxel and vincristine, and this is, at least in part, due to activation of the PI3K/Akt pathway mediated by the XBP-1 axis of the unfolded protein response (UPR). Treatment with the ER stress inducer tunicamycin or thapsigargin before the addition of docetaxel or vincristine reduced the levels of apoptosis induced by the drugs. This was associated with inhibition of mitochondrial release of apoptogenic proteins and activation of Bax and Bak. Induction of ER stress resulted in rapid activation of the PI3K/Akt pathway that appeared to be important in antagonizing docetaxel and vincristine, in that inhibition of Akt by either a PI3K inhibitor or siRNA knockdown of Akt3 blocked the effect of pretreatment with tunicamycin on apoptosis induced by the drugs. Neither docetaxel nor vincristine triggered ER stress in melanoma cells, but the basal activity of XBP-1 signaling seemed to play a role in protection against the drugs, as siRNA knockdown of XBP-1 enhanced docetaxel- and vincristine-induced apoptosis. In addition, inhibition of XBP-1 decreased the constitutive levels of activation of Akt, and blocked activation of Akt induced by tunicamycin. Taken together, these results identify activation of the PI3K/Akt pathway by XBP-1-mediated signaling of the UPR as a resistance mechanism against docetaxel and vincristine in melanoma cells under ER stress.