Past studies have shown that melanoma cells have largely adapted to endoplasmic reticulum (ER) stress, and this is associated with up-regulation of the anti-apoptotic proteins Bcl-2 and Mcl-1. In this report we show that the BH3 mimetic obatoclax potently overcomes resistance of melanoma cells to apoptosis induced by ER stress. Obatoclax as a single agent at nanomolar concentrations was relatively ineffective in induction of apoptosis in melanoma cells, but treatment with obatoclax at these concentrations in combination with the ER stress inducer tunicamycin or thapsigargin markedly enhanced apoptotic cell death. This was primarily due to inhibition of Mcl-1 by obatoclax, in that co-treatment with tunicamycin and another BH3 mimetic ABT737, which does not antagonize Mcl-1, caused only minimal increases in apoptosis. Moreover, over-expression of Mcl-1 inhibited apoptosis to greater degrees than over-expression of Bcl-2. In addition to direct inhibition of Mcl-1 by obatoclax, the combination of obatoclax and tunicamycin caused strong up-regulation of the BH3 only protein Noxa. siRNA knockdown of Noxa partially inhibited apoptosis induced by co-treatment with obatoclax and tunicamycin. Similarly, knockdown of Bak also blocked induction of apoptosis by the compounds. The Mcl-1/Bak interaction appeared to be disrupted more efficiently in melanoma cells co-treated with obatoclax and tunicamycin. Taken together, these results identify obatoclax as a potent agent that overcomes resistance of melanoma cells to ER stress-induced apoptosis, and appear to have important implications in the use of BH3 mimetics in the treatment of melanoma.