Substantial evidence has shown that tumors can emerge from a distinct, small population of cells known as cancer stem cells (CSCs), which have a vital role in the initiation, main­tenance, metastasis, drug resistance, and relapse of cancer. Hence, it is critical to identify drugs that selectively target and eliminate CSCs to induce a long-lasting therapeutic re­sponse and better patient outcomes. Modulations in epige­netic regulation contribute to cancer progression as it is cru­cial for both stem cell biology and chemoresistance. Poly­comb group (PcG) and trithorax group (TrxG) proteins are identified as the key modulators of cellular memory that di­rect whether a stem cell will self-renew or differentiate. The dynamic interaction of these two groups of proteins with op­posing effects on gene expression has opened up new avenues for understanding their role in tumorigenesis. Therefore, it is essential to elucidate the underlying mechanisms of aber­rant epigenetic modifications, without which designing drugs becomes implausible. The existing cancer treatments like ra­diotherapy and chemotherapy have major limitations owing to treatment failure and recurrence of cancer. However, the application of epigenetic therapy has shown promising ther­apeutic results in clinical trials with its ability to reverse the aberrant epigenetic modifications that result in cancer and chemotherapy resistance. Future research aimed at devel­oping drugs that are target specific is necessary to prevent off-target effects. To overcome the limitations of the current epidrugs, novel approaches like CRISPR/Cas9-based epige­netic editing are emerging as new hopes for targeted therapy in cancer. This article gives an overview of the till-date under­standing of the role of epigenetics in cancer stem cell biology and recent developments in epigenetic therapy.