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In the last two decades, thanks to the data that have been obtained from the Human Genome Project and the development of next-generation sequencing (NGS) technologies, research in oncology has produced extremely important results in understanding the genomic landscape of pediatric cancers, which are the main cause of death during childhood. NGS has provided significant advances in medicine by detecting germline and somatic driver variants that determine the development and progression of many types of cancers, allowing a distinction between hereditary and non-hereditary cancers, characterizing resistance mechanisms that are also related to alterations of the epigenetic apparatus, and quantifying the mutational burden of tumor cells. A combined approach of next-generation technologies allows us to investigate the numerous molecular features of the cancer cell and the effects of the environment on it, discovering and following the path of personalized therapy to defeat an "ancient" disease that has had victories and defeats. In this paper, we provide an overview of the results that have been obtained in the last decade from genomic studies that were carried out on pediatric cancer and their contribution to the more accurate and faster diagnosis in the stratification of patients and the development of new precision therapies. [ABSTRACT FROM AUTHOR]