Inhibitory properties of PD-1 receptor engagement on activated T cells are well established in physiologic and pathological contexts. In cancer, the use of checkpoint blockade, such as anti-PD-1 antibodies, becomes progressively a reference treatment of a growing number of tumors. Nonetheless, it is also established that PD-1 expression on antigen-specific T cells reflects the functional avidity and anti-tumor reactivity of these T cells. We will discuss this dual significance of PD-1 expression on tumor-specific T cells, due to a complex regulation and the opportunity to exploit this expression to define, monitor and exploit tumor-reactive T cells for immunotherapy purposes.