The management of renal cell carcinoma (RCC) has undergone rapid and radical evolution over the last few years. An improved understanding of the underlying biology of RCC has led to the approval of several new therapies directed against specific and relevant biological targets, so-called "targeted therapies." These highly effective treatments are now entering routine use, however many questions still remain as to how best to use these agents and integrate them into the broader therapeutic armamentarium. This review summarizes the major published clinical trials of the new agents, discusses the controversies and research questions that have arisen as a result, and considers some of the issues that remain.