Cytoreductive nephrectomy can be an important and effective component of a multidisciplinary treatment approach to metastatic renal cell carcinoma in carefully selected patients. The results of retrospective single institution series and randomized multicenter phase III trials suggest that removal of the primary tumor, even in the setting of metastatic disease, can significantly prolong survival and delay time to progression. It may also enhance the response to systemic therapy in the postoperative period. When employing initial cytoreductive nephrectomy as part of an overall treatment approach, careful patient selection is critical to success. A poor performance status (ECOG performance status less than 1), significant comorbidities that make surgical intervention high risk, or high-volume metastatic disease, and the presence of brain, liver, or bone metastases, or of atypical (sarcomatoid) histology have all been shown to be associated with an extremely poor prognosis. Patients exhibiting these clinical phenotypes should not be considered for initial cytoreductive nephrectomy as part of their treatment paradigm. Instead, they should receive some form of upfront systemic therapy (immunotherapy or novel therapy) and then be considered for delayed nephrectomy as part of a surgical consolidation approach after an interval of treatment if their disease kinetics demonstrate stable or regressing disease in response to systemic therapy. Patients who do not demonstrate these poor prognostic features should be considered for upfront cytoreductive nephrectomy as part of their overall treatment approach because of the potential it offers for palliation from local tumor symptoms, a delay in the time to disease progression, an improved response to systemic therapy, and improved overall survival.