In this study, we have systematically investigated (i) the actual differentiation phenotype of the KDM5Bhigh melanoma persister state, (ii) the consequences of forcing melanoma cells to ectopically express KDM5B at high levels without the chance to spontaneously revert to normal expression heterogeneity and (iii) whether KDM5B-directed cell state transitioning can be used as a therapeutic vulnerability. The gene discussed is KDM5B; the disease is melanoma.