Cytoreductive nephrectomy (CN) has an established role against metastatic renal cell carcinoma (mRCC) in properly selected patients and offers a survival advantage when performed prior to cytokine therapy. With the emergence of new, effective targeted molecular therapies for mRCC, well-designed prospective trials are needed to clarify the biologic effects of CN to determine when and for whom CN should be performed in the context of targeted systemic therapy. Consequently, a thorough characterization of the systemic effects afforded by CN is imperative for developing individualized treatment strategies that effectively address the underlying biology of mRCC while maximizing patient quality of life during therapy. Until then, debulking surgery, which provides a survival benefit for select patients with mRCC, should continue to be used in patients before or after targeted systemic therapy.