The role of nephrectomy in the setting of metastatic renal cell carcinoma has long been controversial and has continued to evolve over the last two decades. The practice of cytoreductive nephrectomy has only recently been widely accepted following the publication of 2 large multi-center randomized controlled trials that established a survival benefit for those patients undergoing nephrectomy followed by interferon treatment. Half a decade later, the new paradigm looks set to be questioned with the rapid emergence of tyrosine kinase inhibitors (TKIs). This article reviews the evolution of cytoreductive nephrectomy and speculates on its role in the new frontier of molecular targeting for metastatic renal cell carcinoma.