<p>Current T cell-based immunotherapy strategies, including immune checkpoint blockade (ICB) and chimeric antigen receptor (CAR) T cells, have revolutionized cancer care. However, many patients with cancer who are treated with these approaches fail to respond or do not achieve durable protection against disease relapse, highlighting the need for further optimization of such strategies. The advent of cancer immunotherapy has ushered in an era of research centred on immune oncology with a specific focus on defining T cell-intrinsic mechanisms that delineate therapeutic responders and non-responders. Among the major barriers limiting immunotherapy efficacy, T cell exhaustion — which is characterized by repression of the effector functions and proliferative potential of T cells — has emerged as a common mechanism among various cancers. Here, we review transcriptional and epigenetic mechanisms that control T cell exhaustion. We discuss how T cell subset-specific gene regulatory programmes limit immunotherapy success and theorize on the development of next-generation strategies for increasing the clinical breadth, efficacy and durability of T cell immunotherapy.</p>