The landscape of treatment for metastatic renal cell carcinoma (mRCC) continues to evolve. Although several new drugs have been approved for the treatment of this disease in recent years, mRCC remains incurable. Thus, the search continues for new effective therapies. One such novel compound is axitinib (Inlyta, Pfizer), a potent vascular endothelial growth factor receptor tyrosine kinase inhibitor. Following phase I testing in advanced solid tumors (where hypertension, stomatitis, and diarrhea were the dose-limiting toxicities), use of axitinib has been further developed through phase II testing in thyroid, breast, lung, and renal cancers. Recently, the phase III AXIS (Axitinib [AG 013736] as Second Line Therapy for Metastatic Renal Cell Cancer) trial demonstrated an improvement in progression-free survival for patients with mRCC who were treated with axitinib versus sorafenib (Nexavar, Bayer) as second-line therapy. This article describes the preclinical and clinical evolution of axitinib, with an emphasis on its development and role in mRCC.