The study investigates the mechanisms of drug resistance in melanoma cells, focusing on rare cell variability and epigenetic reprogramming. Melanoma cells exhibit significant transcriptional variability at the single-cell level, with a small percentage of cells expressing resistance markers at high levels. This variability is transient and can be induced by drugs, leading to epigenetic reprogramming that converts these cells into stably resistant states. The reprogramming involves loss of differentiation and activation of new signaling pathways, primarily mediated by Jun-AP-1 and TEAD. The findings suggest that resistance acquisition occurs in two stages: first, rare cells become transiently pre-resistant, and then, upon drug exposure, they undergo cellular reprogramming to achieve stable resistance. The study also demonstrates that this rare-cell expression pattern is not unique to melanoma and is observed in other cancer types, indicating a general rare-cell expression program. These insights provide a framework for understanding resistance dynamics and may inform therapeutic strategies, including interval dosing and targeting lipid peroxidase pathways.The study investigates the mechanisms of drug resistance in melanoma cells, focusing on rare cell variability and epigenetic reprogramming. Melanoma cells exhibit significant transcriptional variability at the single-cell level, with a small percentage of cells expressing resistance markers at high levels. This variability is transient and can be induced by drugs, leading to epigenetic reprogramming that converts these cells into stably resistant states. The reprogramming involves loss of differentiation and activation of new signaling pathways, primarily mediated by Jun-AP-1 and TEAD. The findings suggest that resistance acquisition occurs in two stages: first, rare cells become transiently pre-resistant, and then, upon drug exposure, they undergo cellular reprogramming to achieve stable resistance. The study also demonstrates that this rare-cell expression pattern is not unique to melanoma and is observed in other cancer types, indicating a general rare-cell expression program. These insights provide a framework for understanding resistance dynamics and may inform therapeutic strategies, including interval dosing and targeting lipid peroxidase pathways.