Signaling through programmed death 1 (PD-1) expressed by activated T lymphocytes inhibits their function and is a major mechanism for suppressing antitumor T cell responses in the tumor microenvironment. Recent clinical trials show that blockade of the B7-H1(programmed death ligand 1 [PD-L1])/PD-1 pathway with anti-PD-1 or anti-PD-L1 is active in several malignancies and produces durable responses in a subset of patients. Clinical response to these agents may be limited by other mechanisms of T-lymphocyte suppression in the tumor microenvironment, or absence of a significant tumor-specific T cell response in the tumor. Combinations with other therapies are likely to address at least several of the major mechanisms of resistance, supported by abundant preclinical data in animal tumor model systems. The combination of anti-PD-1 with anti-CTLA-4 demonstrated promising activity in metastatic melanoma and is being tested in multiple other malignancies. Other combinations based on PD-1/PD-L1 blockade are either in early clinical development or in planning stages. Many of the combinations based on PD-1/PD-L1 blockade are expected to produce a higher incidence of autoimmune-like toxicities, but clinical experience with agents such as ipilimumab suggests that toxicities will be manageable and reversible and the overall risk-benefit ratio will be acceptable.