Phenotypic divergence of sub-populations of tumour cells is known to underpin alternative behaviors linked to tumour progression such as proliferation, survival and invasion. Heterogeneity between two transcription factors in melanoma cells, BRN2 and MITF, has been associated with phenotypic switching between predominantly invasive and proliferative behaviors respectively, thereby allowing adaptation to micro-environmental conditions such as hypoxia, nutrient deprivation and drug treatment. Epigenetic changes, in response to external cues, have been proposed to underpin this process, however the mechanism by which the phenotypic switch occurs is unclear. We have recently identified the NFIB transcription factor as a novel downstream effector of BRN2 function in melanoma cells linked to the migratory and invasive characteristics of these cells. Furthermore, the function of NFIB appears to drive an invasive phenotype through an epigenetic mechanism achieved via the upregulation of the polycomb group protein EZH2. A notable target of NFIB mediated up-regulation of EZH2 is decreased MITF expression, which further promotes a less proliferative, more invasive phenotype. Together our data reveal that NFIB has the ability to promote dynamic changes in the chromatin state of melanoma cells to facilitate migration, invasion and metastasis. Additionally, our data suggests BRN2 co-ordinates survival responses to environmental cues such as hypoxia and nutrient deprivation and alter metabolic functions of the BRN2-high invasive sub-population. Notably, distinct metabolic changes driven by BRN2 offer a potential targeting strategy using novel anticancer agents, dubbed ‘mitocans’, that de-stabilize mitochondrial function.