Advances in experimental therapeutics linked to foundational insights into the biology of conventional renal cell carcinoma (CRCC) have led to significant progress in the control of metastatic CRCC. Transcriptional upregulation of vascular endothelial growth factor A (VEGFA) by hypoxia-inducible factor α (HIF2α) in Von Hippel-Lindau (VHL)-inactivated CRCC results in an angiogenic response, a pathological hallmark of the disease. In parallel, the long-known immunogenic potential of CRCC has been traced by whole-exome sequencing to the highest rates of small insertion and deletion frameshift mutations (indels) among solid tumor types surveyed, and separately, to the activation of endogenous retroviral sequences. The logical combination of VEGF receptor tyrosine kinase inhibitors (VEGFR-TKIs) together with immune checkpoint inhibitors (ICI), or dual CTLA-4 and PD-1 ICI therapy, has fundamentally reshaped long-term survival outcomes of patients with metastatic CRCC. Advances in medicinal chemistry have facilitated successful pharmacological inhibition of HIF2α transcriptional function. While combinatorial therapies remain the current focus of drug development, predictive biomarkers have not supplanted or supplemented clinical risk-stratification tools for therapy selection. Challenges remain to optimize neoadjuvant and adjuvant therapy in high-risk localized disease and to define effective second and third-line management strategies in metastatic CRCC beyond these therapeutic classes. Deeper insights into biological heterogeneity and therapeutic resistance will be required to advance the field.