Molecularly-targeted therapies have revolutionized the treatment of metastatic renal cell carcinoma (mRCC), but unmet needs remain. Efficacy of targeted agents is transient, and questions regarding optimal sequencing of therapies and benefits versus risks of combination therapy remain largely unanswered. In this article, an overview of ongoing/recently completed clinical trials evaluating sequential treatment strategies and combination therapy regimens is presented, along with a brief discussion of predictive biomarkers and prognostic factors. Several ongoing/recently completed clinical studies have been designed to help address 2 major questions currently facing physicians treating patients with mRCC: 1) What is the optimal sequence of targeted agents? and 2) Does combination therapy with targeted agents benefit patients with mRCC? Results of these trials may help establish the degree to which cross-resistance between agents occurs and which agents, when used consecutively, are associated with the most favorable outcomes. Clinical trial data maturing in the next 1-2 years should provide insight into the most effective treatment sequences and the benefits versus risks of combination therapies. Whether results of these studies will lead to a paradigm shift in treatment recommendations for patients with mRCC remains to be determined.