We profiled a large heterogeneous cohort of matched diagnostic relapse tumor tissue and paired plasma-derived cell-free DNA (cfDNA) from patients with relapsed and progressive solid tumors of childhood. Tissue and cfDNA sequencing results were concordant, with a wider spectrum of mutant alleles and higher degree of intratumor heterogeneity captured by the latter, if sufficient ctDNA was present. Serial tumor sequencing identified putative drivers of relapse, with alterations in epigenetic drivers being a common feature. In keeping with epigenetic alterations being a common driver of many childhood cancers, fragmentomic analysis of cfDNA identified tumor-specific epigenetic states and transcription factor binding sites accessible in chromatin. This study leverages a large and well-annotated genomic dataset of aggressive childhood malignancies, identifies genomic and epigenetic drivers of childhood cancer relapse, and highlights the power and practicality of cfDNA analysis to capture both intratumoral heterogeneity and the epigenetic state of cancer cells. In tumors of childhood, we identify mutations in epigenetic genes as drivers of relapse, with matched cfDNA sequencing showing significant intratumor genetic heterogeneity and cell-state specific patterns of chromatin accessibility. This highlights the power of cfDNA analysis to identify both genetic and epigenetic drivers of aggressive disease in pediatric cancers.