Since the approval of immunotherapy checkpoint inhibitors for first-line treatment of metastatic renal cell carcinoma, new and clinically relevant questions have emerged that ongoing clinical trials and trials in development will address. These questions include how to integrate combination immunotherapy approaches like ipilimumab/nivolumab with targeted therapies against vascular endothelial growth factor (VEGF) receptors, which patients can discontinue treatment, and who needs ipilimumab to maximize clinical responses. Furthermore, with new approvals of treatment regimens combining checkpoint inhibitors with targeted therapies, new questions arise in the clinic regarding optimal treatment selection for first-line clear cell renal cell carcinoma. This review will highlight the contemporary clinical trials in metastatic clear cell renal cell carcinoma that try to address some of these knowledge gaps.