Background: Several targeted therapies (TTs) have become available in mRCC in recent years for first- and second-line use, including sorafenib (So), sunitinib (Su), bevacizumab (Be), temsirolimus (Te), everolimus (Ev), pazopanib (Pa), and most recently, axitinib (Ax). This study aimed to examine the current treatment patterns in mRCC patients who fail second-line therapy. Methods: Data were obtained from a large national U.S. claims database for patients with an RCC diagnosis and at least 3 lines of TT between January 1, 2004, and June 30, 2011. Patients were age 18 or older at diagnosis with at least 3 months of follow-up prior to initiation of third-line therapy. Patient characteristics and treatment patterns were examined for the final population. Results: A total of 812 mRCC patients initiated third-line therapy with So, Su, Be, Te, Ev, or Pa. The sample was majority male (70%) with a mean age of 60 years (SD=10.7). A large proportion of patients were from the South (42%), and the majority of the sample (72%) had commercial insurance. The most common sites of metastases at any time were lung (71%) and bone (52%). The most common first-line agent was Su (52%) and the most common second-line single agents were Te (25%) and Ev (17%). The most frequently used single-agents in third-line were Te (21%) and Ev (19%). Third-line treatment choice differed by year; Te (51%) was most common in 2007 while Ev and Pa were most common between 2009 and 2011. Additionally, the most frequently prescribed sequences of single agents were VEGF→mTOR→VEGF (25%), VEGF→mTOR→mTOR (25%), and VEGF→VEGF→mTOR (22%). Conclusions: The results demonstrate a rapidly changing therapeutic scenario for mRCC in the United States. The number of targeted therapies prescribed in third-line increased from 1 in 2006 to 4 in 2007 and 6 in 2011. This evolution of third-line therapies is possibly due to physicians adapting their practice with the advent of novel mRCC treatment options. These results are in line with the NCCN guidelines, with VEGF and mTOR being the most commonly prescribed first- and second-line single agents, respectively.