The optimal management approach to advanced or metastatic renal cell cancer of the clear cell type continues to rapidly evolve. Risk stratification of patients into favorable-, intermediate-, and poor-risk categories is now routinely performed. In selected individuals with low-volume indolent disease, active surveillance may be an appropriate option. Cytoreductive nephrectomy and/or surgical metastasectomy may be also be considered for selected patients after evaluation by a multidisciplinary tumor board. Systemic frontline therapy options now include immune checkpoint inhibitor-based combination (IBC) therapies such as pembrolizumab/axitinib, nivolumab/ipilimumab, and avelumab/axitinib. With unusual exceptions, monotherapy with vascular growth factor receptor tyrosine kinase inhibitors or mTOR inhibitors are no longer appropriate options in the frontline setting. Despite the established efficacy of frontline IBC, most patients will ultimately require additional lines of therapy, and oncologists must think carefully when switching to another therapy, particularly in situations of drug intolerance or apparent disease progression. Systemic therapy options after IBC are generally tyrosine kinase inhibitor-based, and ongoing clinical trials will help optimize the treatment algorithm further. Despite many recent drug approvals for renal cell cancer (RCC), there remains a pressing must identify new therapeutic targets. Finally, other systemic therapy or supportive care approaches must be considered for special patient populations such as those with poor performance status, end-organ dysfunction, brain metastases, or who have undergone metastasectomy.