As　commented　by　the　Nobelist　James　Black　that　“The　most　fruitful　basis　of　the　discovery　of　a　new　drug　is　to　start　with　an　old　drug”,　drug　repurposing　represents　an　attractive　drug　discovery　strategy.　Despite　the　success　of　several　repurposed　drugs　on　the　market,　the　ultimate　therapeutic　potential　of　a　large　number　of　non-cancer　drugs　is　hindered　during　their　repositioning　due　to　various　issues　including　the　limited　efficacy　and　intellectual　property.　With　the　increasing　knowledge　about　the　pharmacological　properties　and　newly　identified　targets,　the　scaffolds　of　the　old　drugs　emerge　as　a　great　treasure-trove　towards　new　cancer　drug　discovery.　In　this　review,　we　summarize　the　recent　advances　in　the　development　of　novel　small　molecules　for　cancer　therapy　by　scaffold　repurposing　with　highlighted　examples.　The　relevant　strategies,　advantages,　challenges　and　future　research　directions　associated　with　this　approach　are　also　discussed.　©　2016　Bentham　Science　Publishers.