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The PD-1 pathway delivers inhibitory signals that function as a brake for immune responses and has wide-ranging immunoregulatory functions. This pathway regulates the critical balance between stimulatory and inhibitory signals needed for effective immune responses to microbes and tumors, as well self-tolerance. The critical role of PD-1 in limiting anti-tumor immunity is demonstrated by the transformative effects of PD-1 cancer immunotherapy. Although PD-1 pathway inhibitors are revolutionizing cancer treatment, mechanistic insights are needed to understand why PD-1 pathway blockade works or fails in order to identify responders to PD-1 cancer immunotherapy and to develop rational combination therapies. This talk will discuss studies in mouse models that have identified mechanisms by which the PD-1 pathway regulates anti-tumor T cell responses, and gene perturbation approaches to discover new cancer immunotherapy targets and their mechanisms of action.