Cancer stem cells (CSCs) possess the ability to self-renew, give rise to differentiated progeny, slowly replicate, and demonstrate resistance to chemo-therapy and radiotherapy. Studies have shown that epigenetic changes, which are reversible changes to genes which do not change the DNA sequence, play a key role in giving CSCs the before mentioned characteristics. These epigenetic changes include histone modification of the ATP-binding cassette (ABC) family of transporters, DNA methylation causing silencing of tumor suppressor genes, chromatin remodeling moving nucleosome at key sites implicated in pluripotency, and noncoding RNA deregulation of key pathways implicated in stemness which results in the propagation and pathogenicity observed in CSCs. The stemlike properties and ability to repopulate tumors make the eradication of CSCs imperative for treating cancer. Clinical trials are now targeting the epige-netic mechanisms which give CSCs the ability to persist through cancer treat-ment. Epigenetic targeting dugs show promising clinical trial results as they combat the resistant nature of CSCs due to their frequent epigenetic changes.