Development of resistance to therapy is common in melanoma irrespective of whether the treatment is with BRAF/MEK inhibitors , immunotherapy or chemotherapy. We have shown previously that pan histone deacetylase inhibitors (HDACi ) can overcome, at least partially, resistance to TRAIL and to selective BRAF inhibitors like Vemurafenib in assays of apoptosis. This was associated with upregulation of the pro apoptotic BH3 only protein Bim and downregulation of XIAP, Bcl-X and Mcl-1. The development of resistance in melanoma to selective BRAFi and immunotherapy with T cells can, in some melanoma, be attributed to paracrine or autocrine stimulation of resistance pathways. We show that this appears related to activation of NF-kB and its downstream target genes. We further show that this activation is dependent on co activation of NF-kB and its target genes by Bromodomain and extraterminal domain (BET) protein containing complexes that read and inhibit acetylated histones in chromatin. The role of the ATPase BRG1 in this inhibition is under study but may implicate the SWI/SNF complex in these interactions. Treatment of melanoma with BET protein inhibitors I-BET151 or JQ1 have proven effective inhibitors of NF-kB and trigger apoptosis of melanoma by upregulation of Bim and regulation of other apoptosis regulators. We suggest that understanding the interplay between transcription factors and chromatin co-activators provides treatment approaches that may be effective against a range of inhibitory mechanisms in melanoma.