Despite current advances in treatment of malignant melanoma, therapy options are still limited. Targeting epigenetic regulators recently emerged as a new therapeutic strategy which allows activation of genes that promote apoptosis and cell death. In this respect, inhibition of histone deacetylases (HDAC) or bromodomain and extra-terminal (BET) proteins has been shown to exert antimelanoma activity, by inducing apoptosis, cell cycle arrest and inhibition of tumor growth in vivo. Here we investigated whether co-treatment of HDAC inhibitor Panobinostat (LBH589) with BET protein inhibitor I-BET151 can potentiate sensitivity of melanoma cells to apoptosis. Combining both LBH589 and I-BET151 caused high levels of cell death, even in melanoma cell lines that were relatively resistant to both drugs alone, but did not affect melanocytes. A combination index study showed the combination was highly synergistic in melanoma cells. Moreover combination of LBH589 and I-BET151 significantly inhibited tumor growth of human melanoma xenografts. To address the mechanism of apoptosis, we examined changes in pro- and anti-apoptotic protein expression in different melanoma cell lines. The majority of cell lines showed increased levels of the BH3 pro-apoptotic protein BIM and decreased expression levels of the anti-apoptotic proteins Bcl-2, Bcl-xl and XIAP. Knockdown of BIM protein expression resulted in a significantly reduced amount of apoptotic cells which points to its involvement in triggering apoptosis. Furthermore the apoptotic effect was accompanied by depolarization of the mitochondrial membrane and cleavage of caspase 3, 7, 9 and PARP. Treatment with caspase inhibitor prevented melanoma cells from apoptosis, indicating that cell death induced by LBH589 and I-BET151 required caspase activity. These results highlight co-targeting of histone deacetylases and BET proteins as a potentially efficacious therapy of malignant melanoma.