Epigenomics investigates heritable modifications to DNA and associated proteins that regulate gene expression without altering the underlying nucleotide sequence. In cancer, aberrant epigenetic landscapes—primarily involving DNA methylation, histone modifications, and non-coding RNAs—disrupt normal transcriptional programs, thereby promoting tumorigenesis, progression, invasion, metastasis, and therapeutic resistance. DNA methylation, predominantly at CpG islands in promoter regions, frequently leads to hypermethylation and subsequent silencing of tumor suppressor genes, while global hypomethylation can activate oncogenes and contribute to genomic instability. Histone modifications, including acetylation, methylation, phosphorylation, and ubiquitination, dynamically alter chromatin structure and accessibility; for instance, aberrant hyperacetylation or altered methylation patterns (such as reduced H4K16 acetylation or H4K20 trimethylation) remodel chromatin to favor oncogenic gene expression or repress tumor-suppressive pathways. Non-coding RNAs, encompassing microRNAs, long non-coding RNAs, and others, further modulate epigenetic machinery by recruiting chromatin-modifying complexes, influencing DNA methylation, histone marks, and chromatin remodeling, thus regulating both oncogenic and tumor-suppressive networks. A hallmark of epigenetic alterations is their reversibility, distinguishing them from irreversible genetic mutations. This property positions epigenetic changes as promising targets for therapeutic intervention and as potential biomarkers for early detection, prognosis, disease monitoring, and treatment response prediction. Epigenetic therapies, such as DNA methyltransferase inhibitors (e.g., 5-azacytidine) and histone deacetylase inhibitors, have gained regulatory approval for certain hematologic malignancies and are under active investigation in solid tumors, including combination regimens to enhance efficacy and overcome resistance. This chapter provides a comprehensive overview of epigenetic mechanisms in cancer, emphasizing their dysregulation, diagnostic and prognostic utility, and emerging therapeutic strategies to exploit reversible epigenetic reprogramming for improved clinical outcomes in oncology.