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Epigenetic mechanisms play a pivotal role in controlling gene expression and cellular plasticity in both normal physiology and pathophysiological conditions. These mechanisms are particularly important in the regulation of stem cell self-renewal and differentiation, both in embryonic development and within adult tissues. A prime example of this finely tuned epigenetic control is observed in the gastrointestinal lining, where the small intestine undergoes renewal approximately every 3-5 days. How various epigenetic mechanisms modulate chromatin functions in intestinal stem cells (ISCs) is currently an active area of research. In this review, we discuss the main epigenetic mechanisms that control ISC differentiation under normal homeostasis. Furthermore, we explore the dysregulation of these mechanisms in the context of colorectal cancer (CRC) development. By outlining the main epigenetic mechanisms contributing to CRC, we highlight the recent therapeutics development and future directions for colorectal cancer research.