Cancer is a loss of cellular homeostasis where epigenetic dysregulation drives adaptation and resistance beyond what genetic mutations alone can explain. 5-methylcytosine (5mC) is uniquely positioned as a programmable regulatory layer: it is writable, erasable and can be maintained through cell division, enabling persistent transcriptional control without DNA sequence change. While hypomethylating drugs (e.g., azacitidine or decitabine) are clinically established in multiple malignancies, their non-specific, genome-wide mode of action can lead to significant off-target effects and adverse events. CRISPR-based epigenome editors overcome this limitation by enabling locus-specific writing/erasing of 5mC; “hit-and-run” systems such as CRISPRoff further demonstrate that transient delivery can produce durable, heritable silencing. This Review explores emerging therapeutic directions: durable transcriptional suppression of disease-driving genes, reversal of therapy resistance, and immune-cell engineering. We further discuss how artificial intelligence can accelerate progress in editor design, multi-omics data integration, and delivery optimization—ushering in a transition from descriptive epigenetics to testable, mechanism-informed interventions.