Metastatic renal cell carcinoma is associated with a poor prognosis and a median survival time of only 6–12 months. However, the emergence of immunotherapies has rekindled interest in cytoreductive nephrectomy as a therapeutic option. Phase III randomized trials have demonstrated that cytoreductive nephrectomy significantly improves overall survival in selected patients with metastatic renal cell carcinoma treated with interferon immunotherapy. While cytokine-based immunotherapy may be considered the standard systemic therapy, clinical studies are ongoing to develop molecular biomarkers and new therapies with improved efficacy and tolerability. With further advances in our understanding of the pathogenesis, behavior and molecular biology of renal cell carcinoma, cytoreductive nephrectomy, in combination with molecular targeted therapies, may become the new standard of care for patients with metastatic renal cell carcinoma.