This study investigates the interplay between clonal evolution and cellular plasticity in hepatoblastoma (HB), a pediatric liver tumor. Using a single-cell multiomic approach, the researchers identified a continuum of cell states between hepatocytic (sch), liver progenitor (scLP), and mesenchymal (scM) differentiation poles. Chromatin accessibility landscapes revealed gene regulatory networks and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations showed that each genetic subclone displays its own range of cellular plasticity across differentiation states. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neoadjuvant chemotherapy, highlighting the potential of these subclones to resist treatment. The study emphasizes how the interplay of clonal evolution and epigenetic plasticity shapes the response of HB subclones to chemotherapy.This study investigates the interplay between clonal evolution and cellular plasticity in hepatoblastoma (HB), a pediatric liver tumor. Using a single-cell multiomic approach, the researchers identified a continuum of cell states between hepatocytic (sch), liver progenitor (scLP), and mesenchymal (scM) differentiation poles. Chromatin accessibility landscapes revealed gene regulatory networks and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations showed that each genetic subclone displays its own range of cellular plasticity across differentiation states. The most scLP subclones, overexpressing stem cell and DNA repair genes, proliferate faster after neoadjuvant chemotherapy, highlighting the potential of these subclones to resist treatment. The study emphasizes how the interplay of clonal evolution and epigenetic plasticity shapes the response of HB subclones to chemotherapy.