Background: Cytoreductive nephrectomy (CN) has been considered standard management for patients with metastatic renal cell carcinoma (mRCC) for over a decade. This practice, based on evidence from the immunotherapy era, has now come into question with the dramatic shift in management of mRCC patients due to the development and approval of several targeted molecular therapies (TMT). Methods: A comprehensive English language literature review was performed using MEDLINE/PubMed to identify articles and guidelines pertinent to CN in mRCC. Results: Retrospective studies have demonstrated improved survival for patients who underwent CN compared to those that did not; however, these studies suffer from heavy selection bias. Furthermore, the optimal timing of TMT, before or after surgery is not known. Pre-surgical TMT has the advantage of early treatment of metastases, downsizing of the primary, and may be an effective 'litmus test' for the selection of patients for CN based on response to TMT. The results of two ongoing phase III trials (CARMENA and SURTIME) will address much of the controversy on the role of CN and the timing of systemic therapy in the TMT era. In this review, we aim to present the evidence that lead to adoption of CN in the era of immunotherapies as well as the available data about the oncologic benefit of CN in patients with mRCC who receive TMT as their primary systemic therapy. Conclusion: There seems to be an important role for CN in the era of TMT, mostly in patients with favorable risk and where a high percentage of tumor burden can be removed by cytoreductive surgery.