The immune system is capable of recognizing tumors and eliminates many early malignant cells. However, tumors evolve to evade immune attack, and the tumor microenvironment is immunosuppressive. Engagement of PD-1 by PD-L1 or PD-L2 results in attenuated TCR signaling and inhibition of T-cell immune functions. Tumors exploit these immune checkpoint pathways to evade immune eradication. Blockade of the PD-1, PD-L1, and CTLA-4 checkpoints is proving to be an effective and durable cancer immunotherapy in a subset of patients in a broad variety of tumor types by allowing the patient to produce an effective anti-tumor immune response. Expression of PD-L1 by tumor cells or infiltrating immune cells correlates with responsiveness to PD-1 or PD-L1 blockade but is an imperfect biomarker since some patients who do not express PD-L1 still respond. A broad range of other immune modulatory targets has been identified and are potential targets for synergizing with immune checkpoint blockade. Advances in understanding T cell coinhibitory pathways have stimulated a new era of immunotherapy with effective drugs to treat cancer.