Cytoreductive nephrectomy (CN) followed by systemic therapy had been considered the standard of care for metastatic renal cell carcinoma (mRCC) patients since two clinical trials established its role during the cytokines era. With introduction of new and effective drugs, such as vascular endothelial growth factor-targeted therapies, the role of CN started to be challenged. Retrospective studies conducted during the targeted therapy era pointed to better outcomes when CN was associated with systemic treatment, although certain patients with poor risk features did not seem to benefit. Therefore, prospective clinical trials supporting CN were needed. Recently, with the publication of two randomized trials evaluating CN in the targeted therapy era, it has been made clear that patient selection and multidisciplinary discussion are of paramount importance in order to achieve the best outcomes. We reviewed the available literature on the role of CN among mRCC patients, commenting on how to apply the new evidence into clinical practice and providing future perspectives.