: Cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) represent inhibitory immune checkpoints. Combination immune checkpoint inhibitor (ICI) therapy with anti-CTLA-4 plus anti-PD-1 antibodies in preclinical models demonstrated greater anti-tumor effect than therapy with either antibody alone. Based upon this anti-tumor effect, anti-CTLA-4 plus anti-PD-1 antibodies have since been tested in a patients, across tumor types, with advanced malignancies.: Herein we describe the biologic rationale for combining anti-CTLA-4 plus anti-PD-1 antibodies, the early studies which established different treatment schedules of the ICI combination in melanoma, the definitive studies which established the role for anti-CTLA-4 plus anti-PD-1 antibodies in patients with advanced malignancies and the toxicity profiles of these agents. We also discuss several experimental disease settings where combined CTLA-4 and PD-1 blockade is being explored.: We anticipate that combination therapy with anti-CTLA-4 plus anti-PD-1 antibodies will become a treatment standard for patients with cancers both responsive and unresponsive to single agent ICI therapy. Given the toxicity profile, we expect that most patients will be treated with lower doses of anti-CTLA-4 and full doses of anti-PD-1 antibodies, however, there may be instances in which a higher dose of anti-CTLA-4 is preferred.