Cancer arises not only from genetic mutations but also from widespread disruption of epigenetic regulation. Chromatin structure, nucleosome positioning, histone modifications, and DNA methylation collectively shape transcriptional programs, and alterations in any of these layers can drive tumorigenesis. Age- and metabolism-dependent changes in cofactors such as α-ketoglutarate, NAD+ (nicotinamide adenine dinucleotide), and acetyl-CoA impair the function of demethylases, deacetylases, and acetyltransferases, promoting DNA hypomethylation, aberrant histone marks, and chromatin remodeling defects characteristic of both aging and cancer. Tumors typically display global DNA hypomethylation together with promoter hypermethylation of tumor-suppressor genes, a pattern known as CIMP (CpG island methylator phenotype). Mutations in chromatin modifiers (e.g., KMT2A, EZH2, SETD2), histone variants (e.g., H3.3), and DNA methylation regulators (e.g., DNA demethylase (TETs), DNA methyltransferase (DNMTs), IDH1/IDH2) further destabilize transcriptional control and genomic integrity. Epigenetic dysregulation reshapes nuclear architecture, dissolving lamina-associated domains and large organized chromatin K9-modifications (LOCKs), enabling enhancer rewiring, and increasing phenotypic plasticity. These alterations allow cancer cells to transition between epithelial, mesenchymal, stem-like, or drug-tolerant states without new genetic mutations. Because epigenomic error rates exceed genetic mutation rates, epimutations can arise early and drive clonal selection, particularly in childhood cancers. Epigenetic modifiers, mediators, and modulators together form a mechanistic framework linking environmental stimuli, metabolic state, and chromatin-based oncogenic reprogramming.