The dynamics of early drug resistance leading to permanent resistance in melanoma are poorly understood. Melanoma cell lines were exposed to molecular targeted inhibitors like BRAF or MEK inhibitors or chemotherapy at sublethal drug concentrations for over 90 days. Alternatively melanoma cells were exposed to hypoxic conditions or low glucose media. Surviving cells were monitored for the expression of CD271, ALDH activity, differentiation markers, ABCB5, chromatin remodeling, histone demethylases and markers for angiogenesis. Further gene expression analyses, RPPA analyses and in vivo tumorigenicity were performed. Drug exposure, hypoxia or nutrient starvation leads to an early innate cell response in melanoma cells resulting in multi-drug resistance, termed induced drug tolerant cells (IDTC). Transition into the IDTC state seems to be an inherent stress reaction for survival towards unfavorable environmental conditions or drug exposure independent of any subpopulation or cancer stem cell. The response comprises chromatin remodeling, activation of signaling cascades, and markers proposed to be stem cell markers with higher angiogenic potential and tumorigenicity. These changes are characterized by a common increase in CD271 expression concomitantly with loss of differentiation markers such as melan-A and tyrosinase, enhanced ALDH activity and upregulation of histone demethylases. IDTCs show a loss of H3K4me3, H3K27me3 and gain of H3K9me3. Drug holidays at the IDTC state allow for reversion into parental cells re-sensitizing them to the drug they were primarily exposed to. Upon continuous drug exposure IDTCs eventually transform into permanent and irreversible drug resistant cells. Knockdown of CD271 or KDM5B decreases transition into the IDTC state substantially but does not prevent it. Our results suggest a phenotypic shift of parental cells to the induced drug tolerant cell (IDTC) state irrespective of a given subpopulation thus not representing cancer stem cells. Targeting IDTCs would be crucial for sustainable disease management and prevention of acquired drug resistance.