Besides somatic mutations or drug efflux, epigenomic reprogramming leads to acquired drug resistance. We recently have identified early stress-induced multi-drug resistant melanoma cells termed induced drug-tolerant cells (IDTCs) [1 ]. IDTCs were generated over 12 to 16 days in different cancer cell lines including melanoma. A common loss of H3K4me3 and H3K27me3 but gain of the H3K9me3 mark was observed in all cell lines as a distinct response to stresses such as drug exposure to sub-lethal concentrations of targeted- or chemotherapy or nutrient starvation. The epigenetic changes were reversible upon drug holidays. Microarray, qPCR and western blot data confirmed up-regulation of histone methyltransferases and down-regulation of histone demethylases contributing to the accumulation of H3K9me3. Moreover similar differential expression patterns of histone modifiers were observed from matched-patient data by RNA-seq corroborating our in-vitro findings. Inhibition of H3K9me3 by small molecule inhibitor BRD4770 showed a synergistic effect with targeted therapy by enhancing cell death with loss of H3K4me3 and H3K9me3. Probing for DNA methylation as an alternative cause of epigenetic changes of global CG and CpG island methylation showed no significant changes at the IDTC stage compared to parental populations. This suggests that distinct histone methylation patterns rather than DNA methylation drive the transition from parental cells to stress induced drug tolerance in melanoma.