The current standard of care for the management of advanced renal cell carcinoma (RCC) revolves around systemic therapy with molecularly targeted agents. Over the last decade, a total of seven targeted drugs have been approved but, altogether, only exploit two molecular targets in this disease: the vascular endothelial growth factor (VEGF) axis and the mammalian target of rapamycin (mTOR). Introduction of these agents has markedly improved outcomes compared with those in the cytokine era, yet comparatively little progress has been made since registration of the first targeted therapeutics occurred 10 years ago. In this article, we review efforts to improve on this current treatment paradigm. We discuss novel targets in this disease and corresponding new agents under investigation. The article dedicates particular attention to targeted immunotherapeutics, which are rapidly emerging as a new category of interest in this disease. Last, we review current data supporting the use of surgical interventions to improve outcomes in patients with metastatic disease.