The combination of targeted therapy and immunotherapy in the treatment of metastatic renal cell carcinoma (mRCC) has significantly improved outcomes for many patients. There are multiple FDA-approved regimens for the frontline setting based on numerous randomized Phase III trials. Despite these efforts, there remains a conundrum of identifying a biomarker-driven approach for these patients and it is unclear how to predict which patients are most likely to respond to these agents. This is due, in part, to an incomplete understanding of how these drug combinations work. The use of tyrosine kinase inhibitors that have multiple 'off-target' effects may lend themselves to the benefits observed when given in combination with immunotherapy. Further, targeting multiple clones within a patient's heterogenic tumor that are responsive to targeted therapy and others that are responsive to immunotherapy may also explain some level of improved response rates to the combination approaches compared to monotherapies. This review highlights the 5 FDA-approved regimens for mRCC in the frontline setting and offers insights into potential mechanisms for improved outcomes seen in these combination approaches.