Several novel targeted agents are being tested for the treatment of advanced renal cell carcinoma (RCC), and results of phase I and II trials have been encouraging. A recently completed phase III, placebo-controlled study showed that median progression-free survival doubled from 12 weeks to 24 weeks in patients treated with the multi-kinase inhibitor sorafenib (Nexavar) (hazard ratio [HR], 0.44; P < .00001), and approximately three-quarters of patients had some degree of tumor regression. Furthermore, interim analysis showed an estimated 39% improvement in overall survival in sorafenib-treated patients (HR, 0.72; P = .018) and an investigator-assessed response rate of 10%, indicating that many more patients had clinical benefit than had tumor regression qualifying as response by traditional criteria. These data and others have added to the evidence of lack of correlation between response rate and clinical benefit in RCC patients (as well as in other tumor types) treated with targeted therapies. Issues surrounding study endpoints and biologic efficacy markers for molecular targeted agents in RCC are discussed in this article, with a focus on results of the Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGETs).