Simple SummaryNon-coding RNAs (ncRNAs) are functional RNA molecules that occupy a large fraction of the genome but are not translated into proteins. However, they serve key regulatory roles in the regulation of gene expression at the transcriptional and translational levels. Recent studies have suggested that ncRNAs can control gene activity by regulating epigenetic mechanisms. Epigenetic changes can modify genomic DNA and histones, thus influencing gene activity without altering the DNA sequence. Atypical epigenetic modifications in specific tumor-promoting (oncogenes) and tumor suppressors genes can result in cancer development and growth. Pediatric tumors are known to be more prone to epigenetic changes compared to adult tumors. These changes can significantly impact the development and progression of these tumors. The abnormal expression of ncRNAs has been linked to epigenetic alterations and tumor development in various types of pediatric cancers. This review discusses the role of ncRNAs as critical regulators of epigenetic modifications that can drive the malignant phenotype in pediatric tumors. It also provides insights into the therapeutic significance of ncRNAs in targeting epigenetic alterations for the treatment of pediatric cancers.AbstractAccording to the World Health Organization, every year, an estimated 400,000+ new cancer cases affect children under the age of 20 worldwide. Unlike adult cancers, pediatric cancers develop very early in life due to alterations in signaling pathways that regulate embryonic development, and environmental factors do not contribute much to cancer development. The highly organized complex microenvironment controlled by synchronized gene expression patterns plays an essential role in the embryonic stages of development. Dysregulated development can lead to tumor initiation and growth. The low mutational burden in pediatric tumors suggests the predominant role of epigenetic changes in driving the cancer phenotype. However, one more upstream layer of regulation driven by ncRNAs regulates gene expression and signaling pathways involved in the development. Deregulation of ncRNAs can alter the epigenetic machinery of a cell, affecting the transcription and translation profiles of gene regulatory networks required for cellular proliferation and differentiation during embryonic development. Therefore, it is essential to understand the role of ncRNAs in pediatric tumor development to accelerate translational research to discover new treatments for childhood cancers. This review focuses on the role of ncRNA in regulating the epigenetics of pediatric tumors and their tumor microenvironment, the impact of their deregulation on driving pediatric tumor progress, and their potential as effective therapeutic targets.