The treatment of metastatic clear cell renal cell carcinoma (RCC) has evolved significantly over the past two decades with the emergence of vascular endothelial growth factor (VEGF) inhibitors, immune checkpoint inhibitors (ICI) and their combinations, which have largely displaced cytokine therapy. More recently, belzutifan, a HIF-2α inhibitor, has emerged as an active agent and is being evaluated vigorously. The application of these novel agents in the early high-risk ccRCC setting appears promising, with the recent emergence of a role for adjuvant pembrolizumab. Furthermore, the role of MET in driving papillary RCC led to the development of MET inhibitors to improve outcomes. However, despite these advances and improved survival, cure remains elusive for the vast majority of patients with metastatic RCC. Ultimately, cure for most patients will only arrive with better knowledge about the mechanisms of resistance and drivers of tumor growth. Clearly, the development of rational and tolerable combinations of agents may be necessary in most settings. This issue of the Cancer Drug Resistance will take the reader on an exciting journey highlighting emerging information regarding mechanisms of resistance, which may inform us toward developing the next waves of novel treatments.