Introduction: One third of patients diagnosed with renal cell carcinoma (RCC) have evidence of metastatic disease upon diagnosis. An improved understanding of the tumor biology of RCC has resulted in the development of new agents that target vascular endothelial growth factor (VEGF), the VEGF receptor, and the mammalian target of rapamycin (mTOR) [1–5]. The treatment of metastatic RCC has thus dramatically changed from a cytokine-based regimen to a molecularly targeted approach. The currently approved frontline agents for treatment of advanced RCC include sunitinib and pazopanib, which are small-molecule receptor tyrosine kinase inhibitors, and the combination of the anti-VEGF monoclonal antibody bevacizumab and interferon (IFN)-α. Temsirolimus, an mTOR inhibitor, is also approved for advanced RCC, and was tested in patients with poor prognosis [5] as defined by three or more Memorial SloanKettering Cancer Center (MSKCC) criteria (anemia, lactate dehydrogenase level >1.5 times the upper level of normal, hypercalcemia, Karnofsky performance score of <80, and time of <1 year from diagnosis to initiation of systemic therapy) as well a sixth criterion of at least two sites of metastatic disease. Sunitinib was approved after showing an improved progression-free survival (PFS) (11 mo vs 5 mo, P<0.05) as compared to IFN. Bevacizumab plus IFN was approved based on an interim analysis that showed an improved PFS (10.2 mo vs 5.4 mo, P=0.0001) as compared to IFN-placebo in the AVOREN trial [6], and an improved PFS (8.5 mo vs 5.2 mo, P<0.0001) as compared to IFN in the CALGB 90206 trial [7]. The primary endpoint of both studies was overall survival (OS), but at the time of the interim analysis, the OS data had not matured. The final updated results of both trials were recently published in the Journal of Clinical Oncology. Treatment with molecularly targeted agents has for the most part resulted in an improved PFS for patients with metastatic RCC, when compared to IFN therapy or to placebo [1, 2, 6, 7]. However, it has been difficult to conclusively show that OS has also improved. In the final analysis of the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) phase 3 clinical trial, sorafenib failed to show a statistically significant OS advantage over placebo (17.8 mo vs 15.2 mo, HR 0.88, P=0.146) [8]. Similar OS results have been reported in the RECORD-1 phase 3 clinical trial [9] studying everolimus as a salvage option in patients who had progressed on TKI treatments (14.8 mo vs 14.4 mo, HR 0.87, M. Choueiri : E. Jonasch (*) Department of GU Medical Oncology, 1515 Holcombe, Houston, TX 77030, USA e-mail: Ejonasch@mdanderson.org