Insights into renal cell carcinoma (RCC) biology have greatly expanded the treatment armamentarium for metastatic RCC (mRCC). Since 2005, six targeted agents have been approved by the US Food and Drug Administration (FDA) for the management of mRCC, and many new targeted therapies are in development. A number of novel VEGF Inhibitors/Multi-Tyrosine Kinase Inhibitors are currently in various stages of development. New targeted agents with novel mechanisms of action are also being studied, including Histone Deacetylase Inhibitors, Angiopoietin/TIE-2 inhibitors, Carbonic anhydrase IX inhibitors, vaccines, and others. In addition to combining currently available immunologic therapies with emerging agents, researchers are also developing novel immunologic therapies to treat mRCC, including those that block Cytotoxic T-Lymphocyte Antigen 4 (CTLA4). Several trials evaluating combinations and sequential therapy of targeted agents have been published, and several others are underway. Trials of special mRCC populations, including poor-risk disease, non-clear cell RCC (NCC-RCC), and papillary type RCC are further refining the use of targeted treatments. As new targeted agents emerge and therapies with novel mechanisms of action are developed, the treatments options available for metastatic RCC are expected to increase. New therapies will likely have fewer detrimental side effects and better efficacy, leading to better quality of life for patients.