As a component of the American Recovery and Reinvestment Act of 2009, comparative effectiveness (CE) studies have been established as a priority in medical research. In the setting of metastatic renal cell carcinoma (mRCC), the theme of CE research is particularly applicable, given the recent approvals of several targeted agents with somewhat overlapping indications. Herein, ongoing comparative clinical trials are discussed that may resolve clinical equipoise in using these agents. Furthermore, ongoing biomarker analyses are reviewed that may ultimately identify subpopulations with unique benefit from specific targeted therapies. Finally, available cost-effectiveness data for targeted therapies in mRCC are presented. The amalgam of these studies may offer the oncologist greater clarity in clinical decision-making.