This study investigates the interplay between clonal evolution and cellular plasticity in hepatoblastoma (HB) using single-cell multiomics. HB is a pediatric liver tumor with heterogeneous cellular phenotypes that influence clinical outcomes. The research identifies a continuum of HB cell states between hepatocytic (scH), liver progenitor (scLP), and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population. Chromatin accessibility landscapes reveal gene regulatory networks and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing 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 neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy. HB is the most frequent pediatric liver tumor, with a 5-year survival rate near 80% after neo-adjuvant chemotherapy. However, chemo-resistant HB have a poor prognosis. The genomic landscape of HB is relatively simple, with β-catenin activating mutations in almost all tumors, and alterations of the 11p15.5 imprinted locus in ~85% of cases. HB are phenotypically heterogeneous, with three main histological patterns - fetal, embryonal, and mesenchymal - that often coexist within a single tumor. Bulk transcriptomic studies identified three major groups related to histological subtypes. 'Hepatocytic' (H) samples are well-differentiated with fetal histology. 'Liver Progenitor' (LP) samples are less differentiated, more proliferative and associated with embryonal histology. 'Mesenchymal' (M) samples lack liver differentiation features and display mesenchymal cell morphologies. Transcriptomic subgroups display striking spatial and longitudinal heterogeneity, extending the heterogeneity described at the histological level, which reflects the ability of tumor cells to change their phenotype. The molecular mechanisms underlying the plasticity of HB cells remain unknown. In particular, the relative roles of genetic evolution and epigenetic plasticity in shaping HB cell phenotypes has not been investigated. In this work, we integrate whole genome sequencing (WGS) and single-nucleus Multiome, allowing simultaneous profiling of gene expression (RNA-seq) and open chromatin (ATAC-seq) from the same cells, to reconstruct the genetic, transcriptomic and epigenomic evolution of 6 representative HB (~23,000 cells). We explore the diversity of cell states, reconstruct the gene regulatory networks and chromatin changes regulating phenotypic switches, and study the interplay of clonal evolution and cellular plasticity. The study reveals that HB cells display continuous statesThis study investigates the interplay between clonal evolution and cellular plasticity in hepatoblastoma (HB) using single-cell multiomics. HB is a pediatric liver tumor with heterogeneous cellular phenotypes that influence clinical outcomes. The research identifies a continuum of HB cell states between hepatocytic (scH), liver progenitor (scLP), and mesenchymal (scM) differentiation poles, with an intermediate scH/LP population. Chromatin accessibility landscapes reveal gene regulatory networks and the sequence of transcription factor activations underlying cell state transitions. Single-cell mapping of somatic alterations reveals the clonal architecture of each tumor, showing 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 neo-adjuvant chemotherapy. These results highlight how the interplay of clonal evolution and epigenetic plasticity shapes the potential of HB subclones to respond to chemotherapy. HB is the most frequent pediatric liver tumor, with a 5-year survival rate near 80% after neo-adjuvant chemotherapy. However, chemo-resistant HB have a poor prognosis. The genomic landscape of HB is relatively simple, with β-catenin activating mutations in almost all tumors, and alterations of the 11p15.5 imprinted locus in ~85% of cases. HB are phenotypically heterogeneous, with three main histological patterns - fetal, embryonal, and mesenchymal - that often coexist within a single tumor. Bulk transcriptomic studies identified three major groups related to histological subtypes. 'Hepatocytic' (H) samples are well-differentiated with fetal histology. 'Liver Progenitor' (LP) samples are less differentiated, more proliferative and associated with embryonal histology. 'Mesenchymal' (M) samples lack liver differentiation features and display mesenchymal cell morphologies. Transcriptomic subgroups display striking spatial and longitudinal heterogeneity, extending the heterogeneity described at the histological level, which reflects the ability of tumor cells to change their phenotype. The molecular mechanisms underlying the plasticity of HB cells remain unknown. In particular, the relative roles of genetic evolution and epigenetic plasticity in shaping HB cell phenotypes has not been investigated. In this work, we integrate whole genome sequencing (WGS) and single-nucleus Multiome, allowing simultaneous profiling of gene expression (RNA-seq) and open chromatin (ATAC-seq) from the same cells, to reconstruct the genetic, transcriptomic and epigenomic evolution of 6 representative HB (~23,000 cells). We explore the diversity of cell states, reconstruct the gene regulatory networks and chromatin changes regulating phenotypic switches, and study the interplay of clonal evolution and cellular plasticity. The study reveals that HB cells display continuous states