Lenvatinib (LVN) has been appoved to treat advanced renal cell carcinoma, differentiated thyroid carcinoma, hepatocellular carcinoma. Further other cancer types also have been tried in pre-clinic and clinic without approvation by FDA. The extensive use of lenvastinib in clinical practice is sufficient to illustrate its important therapeutic role. Although the drug resistance has not arised largely in clinical, the studies focusing on the resistance of LVN increasingly. In order to keep up with the latest progress of resistance caused by LVN, we summerized the latest studies from identify published reports. In this review, we found the latest report about resistance caused by lenvatinib, which were contained the hotspot mechanism such as the epithelial-mesenchymal transition, ferroptosis, RNA modification and so on. The potential ways to conquer the resistance of LVN were embraced by nanotechnology, CRISPR technology and traditional combined strategy. The latest literature review of LVN caused resistance would bring some ways for further study of LVN. We call for more attention to the pharmacological parameters of LVN in clinic, which was rarely and would supply key elements for drug itself in human beings and help to find the resistance target or idea for further study.