T cell exhaustion is a state of dysfunction in CD8+ T cells during chronic infections and cancer, characterized by the over-expression of inhibitory receptors such as PD-1, CTLA-4, and others. Inhibitors of the PD-1:PD-L1 pathway have shown promise in treating various cancers, but clinical responses are mixed, highlighting the need to understand the mechanisms of PD-1:PD-L1 and its role in immunity. Recent studies have shown that PD-1 blockade can reverse T cell exhaustion, leading to reduced viral or tumor load. The past decade has seen a paradigm shift in cancer treatment with the advent of immunotherapies targeting the immune system. These therapies aim to relieve regulatory mechanisms that restrain tumor-infiltrating T cells. Antibodies targeting inhibitory pathways such as CTLA-4 and PD-1 have demonstrated remarkable clinical success. However, the majority of patients do not experience complete responses upon anti-PD-1 treatment, highlighting the need to better understand the mechanisms of action of PD-1:PD-L1, the role of this pathway in immunity to different tumors, and the molecular and cellular effects of PD-1 blockade. Recent clinical trials have shown that blocking the PD-1:PD-L1 pathway enhances immunity in several cancer types, leading to objective responses in a number of patients. However, the majority of patients do not experience complete responses upon anti-PD-1 treatment, and some do not respond at all, highlighting the need to better understand the mechanisms of action of PD-1:PD-L1, the role of this pathway in immunity to different tumors, and the molecular and cellular effects of PD-1 blockade. T cell exhaustion is a state of dysfunction that commonly occurs during chronic infections and cancer due to the persistence of antigen and inflammation. Failure to eliminate antigen is associated with a progressive loss of T cell effector functions, altered metabolism, and a unique transcriptional program compared to functional effector and memory T cells. Exhaustion is also associated with co-expression of high levels of multiple inhibitory receptors including PD-1, Lag-3, Tim-3, CD160, TIGIT, and others. The normal physiological function of PD-1 is thought to be in limiting immunopathology and promoting tolerance to self antigens. Consequently, PD-1 is not a unique phenotypic marker to selectively define T_EX cells, but can also be expressed by recently activated T_EF cells and T cells rendered tolerant due to encountering autoantigen in the absence of high levels of costimulation and/or inflammation. Recent work showed that PD-1+ CD8+ T cells can be found in healthy adult humans, and these cells did not share the transcriptional program of exhaustion with PD-1+ HIV-specific CD8+ T cells in patients afflicted with HIV or T_EX cells in chronic LCMV in mice. Instead, these cells were capable of producing effector cytokinesT cell exhaustion is a state of dysfunction in CD8+ T cells during chronic infections and cancer, characterized by the over-expression of inhibitory receptors such as PD-1, CTLA-4, and others. Inhibitors of the PD-1:PD-L1 pathway have shown promise in treating various cancers, but clinical responses are mixed, highlighting the need to understand the mechanisms of PD-1:PD-L1 and its role in immunity. Recent studies have shown that PD-1 blockade can reverse T cell exhaustion, leading to reduced viral or tumor load. The past decade has seen a paradigm shift in cancer treatment with the advent of immunotherapies targeting the immune system. These therapies aim to relieve regulatory mechanisms that restrain tumor-infiltrating T cells. Antibodies targeting inhibitory pathways such as CTLA-4 and PD-1 have demonstrated remarkable clinical success. However, the majority of patients do not experience complete responses upon anti-PD-1 treatment, highlighting the need to better understand the mechanisms of action of PD-1:PD-L1, the role of this pathway in immunity to different tumors, and the molecular and cellular effects of PD-1 blockade. Recent clinical trials have shown that blocking the PD-1:PD-L1 pathway enhances immunity in several cancer types, leading to objective responses in a number of patients. However, the majority of patients do not experience complete responses upon anti-PD-1 treatment, and some do not respond at all, highlighting the need to better understand the mechanisms of action of PD-1:PD-L1, the role of this pathway in immunity to different tumors, and the molecular and cellular effects of PD-1 blockade. T cell exhaustion is a state of dysfunction that commonly occurs during chronic infections and cancer due to the persistence of antigen and inflammation. Failure to eliminate antigen is associated with a progressive loss of T cell effector functions, altered metabolism, and a unique transcriptional program compared to functional effector and memory T cells. Exhaustion is also associated with co-expression of high levels of multiple inhibitory receptors including PD-1, Lag-3, Tim-3, CD160, TIGIT, and others. The normal physiological function of PD-1 is thought to be in limiting immunopathology and promoting tolerance to self antigens. Consequently, PD-1 is not a unique phenotypic marker to selectively define T_EX cells, but can also be expressed by recently activated T_EF cells and T cells rendered tolerant due to encountering autoantigen in the absence of high levels of costimulation and/or inflammation. Recent work showed that PD-1+ CD8+ T cells can be found in healthy adult humans, and these cells did not share the transcriptional program of exhaustion with PD-1+ HIV-specific CD8+ T cells in patients afflicted with HIV or T_EX cells in chronic LCMV in mice. Instead, these cells were capable of producing effector cytokines