Resistance to cancer treatments remains a major barrier in developing cancer cures. While promising combination chemotherapy treatments and novel immunotherapies have improved patient outcomes, resistance to these treatments remains poorly understood. New insights into the dysregulation of the epigenome show how it promotes tumor growth and resistance to therapy. By altering control of gene expression, tumor cells can evade immune cell recognition, ignore apoptotic cues, and reverse DNA damage induced by chemotherapies. In this chapter, we summarize the data on epigenetic remodeling during cancer progression and treatment that enable cancer cell survival and describe how these epigenetic changes are being targeted clinically to overcome resistance.