The discovery of immune inhibitory checkpoints has revolutionized the approach to the systemic treatment of cancer. The programmed death 1 (PD-1) inhibitory checkpoint, in particular, has played a key role in understanding how certain cancers can evade immune surveillance. Blocking the interaction between the PD-1 receptor and its primary ligand (PD-L1) has demonstrated remarkable anti-cancer activity, and has led to the recent accelerated approval of two anti-PD-1 drugs for use in unresectable and metastatic melanoma in the USA. Results of these therapeutic advances have solidified the role of immunotherapy in the treatment of melanoma, results that may be applicable to the treatment of other cancers. In this review, we discuss the role of the PD-1 pathway in the immune system and the anti-cancer mechanism of action of inhibiting the PD-1/PD-L1 interaction. We also review the efficacy and safety data of currently approved and in-development anti-PD-1 agents, and explore the next steps to further improve patient outcomes.