Within the past 5 years, the United States Food and Drug Administration have approved six targeted agents for the treatment of metastatic renal cell carcinoma (mRCC). While this offers great potential to patients afflicted with this disease, oncologists are faced with the challenge of applying each agent in the appropriate clinical setting. Doing so requires an intricate understanding of the pivotal trials evaluating these agents. Herein, we have provided a detailed analysis of the study design employed in these trials. Use of appropriate comparator arms for targeted therapies (i.e., interferon-alpha or placebo) is addressed. Furthermore, we discuss the relative merits of using progression-free survival (PFS) or overall survival (OS) as a primary endpoint-importantly, the two endpoints may not be precisely correlated. Strategies to appropriately interpret OS in the context of post-study therapies and crossover designs are described. Ultimately, head-to-head trials comparing targeted therapies are necessary to resolve clinical equipoise. Several ongoing efforts juxtaposing the approved agents for mRCC are discussed.