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Genitourinary malignancies represent a diverse biologic and immunologic landscape. Recently, checkpoint blockade has transformed the treatment paradigms for bladder and kidney cancer. However, continued progress will be essential in bladder and kidney cancer, given response to inhibition of the PD-1/PD-L1 (PD-1/PD-L1) axis remains variable and only a minority of patients respond. In contrast with the clinical trial results in bladder and kidney cancer, studies of anti–PD-1/PD-L1 therapy in prostate cancer have generally been disappointing. Nevertheless, an exciting array of studies is underway that are translating lessons learned from tumor biology into promising clinical trials. Here we highlight important features of the immune tumor microenvironment of bladder, kidney, and prostate cancer and review key completed and ongoing clinical trials of anti–PD-1/PD-L1 therapy in these tumor types.