The role of immune checkpoints in modulating the magnitude as well as the functional profile of T cell responses is increasingly understood in molecular detail. Antibody-mediated blockade of co-inhibitory receptors has been shown to restore T cell function in both chronic viral infections and cancer. The latter has been successfully translated to new therapeutic options in the treatment of cancer. Indeed, monoclonal antibodies blocking either CTLA-4 or PD-1 have recently been approved for the treatment of metastatic melanoma in the United States, Europe and Japan. In this commentary, we summarize and put into perspective five letters recently published back to back in the November 27 (2014) issue of Nature reporting on different immunological and clinical aspects of blockade of the PD-1/PD-L1 pathway in tumor bearing hosts. Notably, treatment with anti-PD-L1 blocking antibody was shown result in profound clinical responses in patients with several solid tumor including bladder, lung and head and neck carcinomas among others. These five simultaneous publications highlight the tremendous therapeutic potential of targeting the PD-1/PD-L1 immune checkpoint and emphasize the need to identify appropriate biomarkers to guide their optimal clinical application.