The past decade has seen the emergence of immunotherapy as a prime approach to cancer treatment, revolutionizing the management of many types of cancer. Despite the promise of immunotherapy, most patients do not have a response or become resistant to treatment. Thus, identifying combinations that potentiate current immunotherapeutic approaches will be crucial. The combination of immune-checkpoint inhibition with epigenetic therapy is one such strategy that is being tested in clinical trials, encompassing a variety of cancer types. Studies have revealed key roles of epigenetic processes in regulating immune cell function and mediating antitumour immunity. These interactions make combined epigenetic therapy and immunotherapy an attractive approach to circumvent the limitations of immunotherapy alone. In this Review, we highlight the basic dynamic mechanisms underlying the synergy between immunotherapy and epigenetic therapies and detail current efforts to translate this knowledge into clinical benefit for patients.