Sorafenib, the first oral multikinase inhibitor, can inhibit several kinases involved in tumor proliferation and angiogenesis including Raf, VEGFR, PDGFR, kit and so on.  Due to the advantages of multi- mechanisms, broad-spectrum anticancer potency, and well-tolerated results in combination trials, more and more researchers have focused on the optimization of sorafenib in order to develop novel multi-targeted anticancer drugs.  The present paper reviews the development of modification of sorafenib in recent years from two aspects: bio-isosterism and scaffold hopping.  The structure-activity relationship (SAR) of these compounds is also summarized.