The　DNA　repair　protein,　O-6-methylguanine　DNA　methyltransferase　(MGMT),　can　confer　resistance　to　guanine　O-6-alkylating　agents.　Therefore,　inhibition　of　resistant　MGMT　protein　is　a　practical　approach　to　increase　the　anticancer　effects　of　such　alkylating　agents.　Numerous　small　molecule　inhibitors　were　synthesized　and　exhibited　potential　MGMT　inhibitory　activities.　Although　they　were　nontoxic　alone,　they　also　inhibited　MGMT　in　normal　tissues,　thereby　enhancing　the　side　effects　of　chemotherapy.　Therefore,　strategies　for　tumor-specific　MGMT　inhibition　have　been　proposed,　including　local　drug　delivery　and　tumor-activated　prodrugs.　Over-expression　of　MGMT　in　hematopoietic　stem　cells　to　protect　bone　marrow　from　the　toxic　effects　of　chemotherapy　is　also　a　feasible　selection.　The　future　prospects　and　challenges　of　MGMT　inhibitors　in　cancer　chemotherapy　were　also　discussed.