© 2014 Future Medicine Ltd. Multiple VEGF and mTOR inhibitors have provided improvements in median progression-free survival for metastatic renal cell carcinoma. Tivozanib is a potent and specific VEGFR-1, -2 and -3 tyrosine kinase inhibitor. Promising results led to the TIVO-I Phase III trial (n = 517) comparing tivozanib with sorafenib in patients who were either untreated or had received cytokines. This study met its primary end point by statistically significantly improving progression-free survival, but did impair overall survival, a secondary end point. Crossover from sorafenib to tivozanib may have confounded survival. Because of that detrimental survival, the US FDA rejected approval in May 2013, leading to interruption in its development for renal cell carcinoma.