The standard approach for managing patients with metastatic renal cell carcinoma consists of a cytoreductive nephrectomy followed by immunotherapy, chemotherapy or a targeted agent. Optimal timing of surgery and systemic therapy is not known, and has not been researched. A number of questions arise. First, in the era of antivascular therapy, is cytoreductive nephrectomy a necessity? Second, is it possible that pretreatment with systemic therapy prior to cytoreductive nephrectomy improves surgical outcome and survival? Third, which agents are best suited for an integration of surgery with systemic therapy, both in the metastatic and the nonmetastatic setting? This review will address each of these questions and summarize ongoing trials that are designed to provide some of the answers.