<p>Frontline systemic therapy for metastatic clear cell renal cell carcinoma (RCC) has evolved to include doublet immunotherapy (IO/IO) and immunotherapy–tyrosine kinase inhibitor combinations (IO/TKI), with selection typically guided by histology and risk stratification. However, optimal regimen selection remains undefined owing to limited head-to-head data. Subanalyses of landmark clinical trials and emerging real-world multicenter study data suggest differential treatment benefit derived by metastatic site, particularly for bone metastases. Evidence suggests that bone metastases promote an immunosuppressive tumor microenvironment and may preferentially upregulate genes encoding angiogenic factors, compared with other sites. Such biology-driven patterns provide a rationale for the hypothesis that IO/TKI may confer greater activity in bone-predominant disease. Liver metastases may also exhibit similar site-specific patterns due to harboring an immunosuppressive and vascular environment, but RCC-specific data remain scarce. This overview summarizes the mechanistic rationale, clinical evidence, and practical implications of tailoring treatment by disease site, highlighting critical gaps as well as future research priorities.</p>