Despite extensive investigation over the past three decades, cancer immunotherapy has produced limited success, with few agents achieving approval by the Food and Drug Administration and even the most effective helping only a minority of patients, primarily with melanoma or renal cancer. In recent years, immune checkpoints that maintain physiologic self-tolerance have been implicated in the down-regulation of anti-tumor immunity. Efforts to restore latent anti-tumor immunity have focused on antibody-based interventions targeting CTL antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) on T lymphocytes and its principal ligand (PD-L1) on tumor cells. Ipilimumab, an antibody targeting CTLA-4, appears to restore tumor immunity at the priming phase, whereas anti-PD-1/PD-L1 antibodies restore immune function in the tumor microenvironment. Although ipilimumab can produce durable long-term responses in patients with advanced melanoma, it is associated with significant immune-related toxicities. By contrast, antibodies targeting either PD-1 or PD-L1 have produced significant anti-tumor activity with considerably less toxicity. Activity was seen in patients with melanoma and renal cancer, as well as those with non-small-cell lung, bladder and head and neck cancers, tumors not previously felt to be sensitive to immunotherapy. The tolerability of PD-1-pathway blockers and their unique mechanism of action have made them ideal backbones for combination regimen development. Combination approaches involving cytotoxic chemotherapy, anti-angiogenic agents, alternative immune-checkpoint inhibitors, immunostimulatory cytokines and cancer vaccines are currently under clinical investigation. Current efforts focus on registration trials of single agents and combinations in various diseases and disease settings and identifying predictive biomarkers of response.