Immune responses are regulated by an exquisite system of checks and balances that enable effective protective immunity and tolerance. A number of immunological checkpoints control cells of the innate and adaptive immune system that determine their function. Stimulatory checkpoint pathways promote activation of naive T cells, as well as effector, memory and regulatory T cell responses. Inhibitory checkpoint pathways limit the threshold for T cell activation and duration of immune responses, and have diverse effects that regulate resolution of inflammation, tolerance and homeostasis. Tumors have hijacked inhibitory checkpoints to evade immune eradication. Blockade of the T cell checkpoint inhibitors CTLA-4 and PD-1 has shown remarkably durable clinical responses, but is effective in only a subset of patients.[1-5] Combination therapy approaches are further improving response rates.[6] These successes have stimulated great interest in determining the roles of innate and adaptive checkpoints in controlling the immunosuppressive tumor microenvironment, and developing strategies to target these checkpoints for cancer immunotherapy.