Despite advances in metastatic renal cell carcinoma (mRCC) treatments, patients 
eventually progress and develop resistance to therapies targeting a single 
pathway. Lenvatinib inhibits VEGFR1-3, FGFR1-4, PDGFRβ, RET and KIT 
proto-oncogenes. In a randomized, Phase II trial evaluating patients with mRCC 
who had progressed after one prior VEGF-targeted therapy, progression-free 
survival was significantly improved with lenvatinib alone or in combination with 
everolimus versus everolimus alone. This review summarizes the clinical 
development of lenvatinib in mRCC, and how simultaneous targeting of multiple 
pathways involved in carcinogenesis and/or therapeutic resistance may improve 
patient outcomes. Lenvatinib plus everolimus may be a promising second-line 
treatment in patients with mRCC.