Metastatic renal cell carcinoma (RCC) is highly resistant to chemotherapy but responds modestly to cytokine therapy. The prognosis for long-term survival is poor. Approximately 10% of patients who present with metastatic disease or relapse after nephrectomy are alive at 5 years. Identification of prognostic or predictive factors for individual patient outcomes is necessary in order to develop tailored treatments that reduce the risk of relapse and enhance the chance of successful management. The relationship between pretreatment clinical features and survival has been evaluated in studies leading to the creation of a Memorial Sloan-Kettering Cancer Center (MSKCC) risk model. Additionally, the cloning of the von Hippel-Lindau tumor suppressor gene, and the elucidation of its role in upregulating growth factors associated with angiogenesis, has provided insight into RCC biology and defined a series of targets for novel therapeutic agents. These targeted agents, including sunitinib, sorafenib, temsirolimus, everolimus, and bevacizumab plus interferon-alpha, have shown benefit in phase III trials in first- and second-line therapy. Analysis of the data from these trials and use of prognostic models have resulted in a new paradigm for the treatment of metastatic RCC. Herein, we review these targeted agents, the MSKCC risk model, and the new paradigm for treatment of metastatic RCC.