Cytoreductive surgery (nephrectomy and/or metastasectomy) has been an established therapeutic consideration for selected individuals with metastatic renal cell cancer (mRCC) of the clear-cell type for more than 2 decades. The efficacy of cytoreductive nephrectomy (CN) was initially confirmed by the Southwest Oncology Group (SWOG) trial S8949, which demonstrated a statistically significant overall survival (OS) benefit for CN vs no CN (median OS, 11.1 vs 8.1 months) in the context of systemic interferon therapy.1 A smaller European Organisation for Research and Treatment of Cancer (EORTC) study, also in the cytokine era, reported a median OS benefit of 10 months associated with CN vs no CN (17 vs 7 months).2 A combined analysis of the SWOG and EORTC trials found that CN was associated with a 6-month absolute median OS benefit (13.6 vs 7.8 months).3 The benefit of CN was more pronounced in patients with a Zubrod performance status (PS) of 0 (17.6 vs 11.7 months) compared with a PS of 1 (6.9 vs 4.8 months). In a multivariate analysis of S8949 patients who had survived at least 90 days after randomization, early progressive disease within 90 days was prognostic of worse OS (hazard ratio, 2.1; P < .001).4 The precise biologic basis for these findings has not been completely defined; as a result, biomarkers to select patients most likely to benefit from CN have not been sufficiently validated. Furthermore, the role of CN in the context of more active systemic therapies, such as vascular endothelial growth factor tyrosine kinase inhibitors, has been unclear until recently.