Acquired drug resistance is a major reason for limited success of multiple drugs including recently introduced molecular targeted therapies, like that of BRAF inhibitors in melanoma. Exposing melanoma cells to different concentrations of PLX4032 resulted in transformation of parent cells into slow proliferative multiple drug tolerant cells characterized by high expression of CD271 and an altered chromatin state. These cells presented with upregulation of SOX10 and downregulation of melanoma antigen markers like Melan-A and Tyrosinase. A sustained rewiring of signaling cascades exhibited by this cell population, termed adaptive drug tolerant cells (ADTCs), renders them multiple-drug tolerant. Exposure to combinations of different drugs, like PLX4032 with inhibitors for IGF1-R, HDAC or Pi3K did not affect survival of ADTCs compared to parent cells. ADTCs did not originate from a particular subpopulation, since sorting of parent cells into CD133+/- or CD271+/- always resulted in high expressing CD271 ADTCs. Under prolonged drug exposure ADTCs re-establish homeostasis in signaling leading to the formation of permanently drug resistant cells with loss of sensitivity towards the drug they primarily were exposed to, but susceptible to other drugs. This shift was observed to be coupled to the loss of CD271 and higher proliferation. Nevertheless the capability to exhibit the trait of transformation into ADTCs is preserved even in permanently drug resistant cells, exemplifying a relentless nature to drug resistance. ADTCs represent a new phenotype of early multiple drug tolerant cancer cells amenable for therapeutic intervention.