Renal cell carcinoma (RCC) is rare, but its prevalence is growing. In its early stages, RCC is often clinically silent, resulting in many patients presenting when their disease has become advanced or metastatic. Even in patients with clinically localized disease, there is a high risk of recurrence following nephrectomy, increasing the risk of poor outcomes. Historically, patients with RCC recurrence or advanced or metastatic disease at diagnosis had few treatment options, as chemotherapy and radiation have been largely ineffective. However, many therapeutic advances in patients with RCC have been made over the past decade, including the approval of several TKIs, which have led to improved outcomes. But, the ever-growing RCC treatment arsenal and increased recognition that RCC is a highly heterogenous disease has added to the challenge of treatment selection in patients with advanced disease. In this activity, a virtual mentor will guide you through the first- and second-line treatment selection for 2 patients with metastatic RCC, who fall at opposite ends of the prognostic spectrum. Both you and your mentor will explore the optimal use of TKIs and checkpoint inhibitors in treating each patient. You will also learn about the adverse effects associated with these treatments and how to mitigate and manage them.