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T cells are critical mediators of anti-viral and anti-tumor immunity. While they have evolved to efficiently deal with acute threats to the organism, they undergo a process termed ‘exhaustion’ in response to chronic challenges such as chronic infection and cancer. T cell exhaustion is characterized by loss of effector function, reduced proliferation and impaired ability to form memory. While this process is required to prevent excessive immune activation and collateral damage during chronic infection it also impairs immunity to cancer. Up-regulation of inhibitory receptors or immune checkpoints, including PD-1, is central to the exhaustion program and blocking PD-1 can re-engage T cell immunity and result in improved tumor control. We and others found that exhausted T cells are maintained by a population of stem-like precursor T (Tpex) cells that retain high proliferative and self-renewal capacity and give rise to both effector and terminally differentiated cells. Critically, Tpex cells also mediate the response to PD-1 blocking therapies and are therefore required for the clinical success of checkpoint inhibitors. In my presentation, I will discuss our current understanding of the cellular and molecular regulators of T cell stemness and exhaustion, which has important implications for the development of new therapeutic approaches to the treatment of infection and cancer.