Ever since T cell exhaustion was initially characterized and thoroughly analyzed in the murine LCMV model, such a functional impairment has been validated in other chronic viral infections such as HIV, HCV, and HBV. In tumor immunology, it has always been postulated that tumor-reactive T cells could also become functionally exhausted owing to the high tumor-antigen load and accompanying inhibitory mechanisms. However, the empirical evidences for this hypothesis have not been as extensive as in chronic infection perhaps because much of the focus on T cell dysfunction in tumor immunology has been, and appropriately so, on breaking or bypassing immune tolerance and anergy to tumor/self antigens. On the basis of recent reports, it is becoming clear that T cell exhaustion also plays a crucial role in the impairment of antitumor immunity. In this review, we will comparatively evaluate the T cell responses in cancer and chronic infection, and the therapeutic strategies and interventions for both diseases.