Krüppel-like　factor　5　(KLF5)　belongs　to　a　family　of　zinc-finger-containing　transcription　factors　which　are　involved　in　regulating　expression　of　a　wide　range　of　genes,　thereby　affecting　diverse　cellular　functions.　The　activities　of　KLF5　are　regulated　by　multiple　signaling　pathways　including　Wnt,　Ras,　TGFβ,　Hippo,　Notch,　retinoid　acid　receptor,　and　hormone　receptors.　The　expression　of　KLF5　is　frequently　abnormal　in　human　cancers　and　the　functions　of　KLF5　are　context　dependent.　Accumulating　evidence　suggests　that　KLF5　represents　a　novel　therapeutic　target　for　cancer　therapy.　In　this　review,　we　discuss　the　potential　biological　functions　of　KLF5　associated　with　several　key　signaling　pathways　that　are　relevant　to　cancer　as　well　as　the　involvement　of　KLF5　in　various　human　cancers.　We　also　describe　the　progress　in　the　discovery　and　development　of　small　molecules　targeting　KLF5　as　potential　therapeutics　that　may　benefit　cancer　patients.　The　challenges　and　future　research　directions　on　the　drug　discovery　of　KLF5　ligands　are　also　presented.　©　2015　Bentham　Science　Publishers.