Immunotherapy-based combinations have had a dramatic improvement in outcomes for patients with metastatic renal cell carcinoma, with some patients having deep and durable responses. Developing biomarkers to predict which patients are most likely to respond to immunotherapy may help limit the number of patients who require upfront and long-term exposure to VEGF-TKIs. Additionally, the identification of biomarkers may help further our understanding of the tumor microenvironment (TME), enabling new mechanisms and combinations to improve outcomes for patients.