DNA-damaging　agents,　such　as　methylating　agents,　chloroethylating　agents　and　platinum-based　agents,　have　been　extensively　used　as　anticancer　drugs.　However,　the　side　effects,　high　toxicity,　lack　of　selectivity　and　resistance　severely　limit　their　clinical　applications.　In　recent　years,　a　strategy　combining　a　DNA-damaging　agent　with　a　bioactive　molecule　(e.g.,　enzyme　inhibitors)　or　carrier　(e.g.,　steroid　hormone　and　DNA　intercalators)　to　produce　a　new　`combi-molecule＇　with　improved　efficacy　or　selectivity　has　been　attempted　to　overcome　these　drawbacks.　The　combi-molecule　simultaneously　acts　on　two　targets　and　is　expected　to　possess　better　potency　than　the　parent　compounds.　Many　studies　have　shown　DNA-damaging　combi-molecules　exhibiting　excellent　anticancer　activity　in　vitro　and　in　vivo.　This　review　focuses　on　the　development　of　combi-molecules,　which　possess　increased　DNA-damaging　potency,　anticancer　efficacy　and　tumor　selectivity　and　reduced　side　reactions　than　the　parent　compounds.　The　future　opportunities　and　challenges　in　the　discovery　of　c-ombi-molecules　were　also　discussed.