Surgical resection remains the cornerstone of treatment for kidney cancer. The cytokines interleukin-2 and interferon-alfa were, at one time, the only available approved systemic therapies for metastatic disease. However, the two agents are toxic when used in high doses and associated with clinical benefit for only a small subset of patients. The approval of targeted agents sunitinib, sorafenib, temsirolimus, and everolimus has offered the possibility of improved outcomes for a greater number of patients. This article reviews surgical options for metastatic renal cell carcinoma as well as clinical trial data on treatment strategies with cytokines and targeted agents.