T-cell exhaustion is a unique state that appears during many chronic infections and cancer and is characterized by loss of proliferative capacity and effector function. Complex mechanisms are involved in this T-cell dysfunction but an inhibitory receptor, PD-1, has been identified as a major regulator of T-cell exhaustion. Blockade of the PD-1 pathway can reinvigorate exhausted T cells, resulting in better control of chronic infections and cancer. Notably, recent clinical studies have revealed that PD-1-directed immunotherapy is highly effective in cancer patients, demonstrating that PD-1 is a promising therapeutic target in humans. In this review, we summarize our current understanding of the epigenetic regulation of PD-1 expression in T cells and discuss potential combination therapy with PD-1 blockade toward developing more effective treatment for chronic infections and cancer.