<p>Therapeutic failure in cancer often arises from the ability of tumor cells to adapt to external stressors such as drug exposure, metabolic and oxidative stress, and immune surveillance within the tumor microenvironment (TME). This adaptive capacity is a significant factor contributing to poor clinical outcomes and the lethality associated with many aggressive cancer types. During tumor progression, a subpopulation of cells may acquire stem-like characteristics, leading to the development of cancer stem cells (CSCs), which play a pivotal role in resistance and disease recurrence. A key driver of this process is epigenetic reprogramming, which alters histone modifications and chromatin architecture in response to environmental stimuli. These modifications activate genes associated with stemness by creating transcriptionally permissive chromatin regions, while simultaneously silencing genes involved in differentiation, thereby maintaining the tumor cells’ undifferentiated state. This cellular plasticity enables cancer cells to undergo transdifferentiation or dedifferentiation, enhancing their capacity for survival and adaptation. Importantly, distinct transcriptional states are often regulated by specific epigenetic signatures, some of which are valuable for tumor subtype classification, prognosis assessment, and treatment response prediction. Furthermore, certain epigenetic biomarkers show considerable promise for detecting tumor recurrence and monitoring minimal residual disease with high sensitivity. In this review, we examine how epigenetic reprogramming influences chromatin plasticity to promote stemness and therapeutic resistance. Additionally, we discuss ongoing translational research aimed at leveraging these mechanisms to advance precision oncology, with the ultimate goal of improving diagnostic accuracy and therapeutic efficacy.</p>