Metastatic renal cell carcinoma (RCC) has traditionally been associated with a poor prognosis with few effective treatments. In the multimodal treatment of metastatic RCC, cytoreductive nephrectomy (CN) became the standard of care after two randomized trials demonstrated a benefit in overall survival in patients who received CN prior to treatment with interferon. More recently, several agents (sunitinib, sorafenib, temsirolimus, everolimus and bevacizumab) have been developed that target angiogenesis and the cellular growth pathways involved in metastatic RCC. These targeted agents have demonstrated improved outcomes compared to cytokine therapy, and have transformed metastatic RCC treatment. Targeted agents are being used as a first-line systemic treatment in patients with metastatic RCC with unprecedented success, and many studies are now focusing on the role of CN in combination with these agents for patients with metastatic RCC.