MET has been considered as a promising drug target for the treatment of MET-dependent diseases, particularly non-small cell lung cancer (NSCLC). Small molecule MET inhibitors with mainly three types of binding modes (Ia/Ib, II, and III) have been developed. In this Review, we provide an overview of the structural features, activation mechanism, and dysregulation pathway of MET and summarize progress on the development and discovery strategies utilized for MET inhibitors as well as mechanisms of acquired resistance to current approved inhibitors. The insights will accelerate discovery of new generation MET inhibitors to overcome clinical acquired resistance.