<p>Therapeutic resistance remains a major cause of treatment failure and disease recurrence across cancer types, considerably limiting the long-term efficacy of chemotherapies, targeted therapies, and immunotherapies. Growing evidence indicates that resistance cannot be fully explained by static genetic alterations but rather arises from dynamic and reversible adaptive processes. Epigenetic regulation governs transcriptional plasticity, cellular state transitions, and tumor heterogeneity under therapeutic stress. Alterations in DNA methylation, histone modifications, chromatin accessibility, and non-coding RNA networks enable cancer cells to silence tumor suppressor programs, activate compensatory survival pathways, acquire stem cell-like drug-tolerant persister states, and remodel the tumor immune microenvironment. These mechanisms often act in a coordinated manner to form a dynamic regulatory system that supports adaptive resistance. However, current studies have frequently focused on individual epigenetic regulators and have lacked an integrated framework to explain how epigenetic plasticity collectively drives therapeutic resistance. In this review, we deconstruct cancer therapy resistance using the conceptual framework of the “epigenetic landscape.” We summarize the molecular functions and crosstalk among the major epigenetic layers and describe how this integrated network sustains key resistance-associated phenotypes. We also discuss emerging therapeutic strategies that target epigenetic plasticity, including epigenetic drugs, targeted protein degradation, epigenetic editing, and rational combination therapies. Overall, this review provides a systematic framework for understanding epigenetically mediated therapy resistance and highlights epigenetic plasticity as a therapeutic vulnerability for developing durable cancer treatments.</p>