Simple　Summary　The　unique　characteristics　of　tumor　energy　metabolism　(highly　dependent　on　aerobic　glycolysis,　namely,　the　Warburg　effect)　make　it　an　interesting　and　attractive　target　for　drug　discovery.　Radio-　and　chemoresistance　are　closely　associated　with　the　Warburg　effect.　Lonidamine　(LND),　as　a　glycolytic　inhibitor,　although　having　low　anticancer　activity　when　used　alone,　exhibits　selectivity　to　various　tumors,　and　its　adverse　effects　do　not　overlap　when　combined　with　other　chemotherapeutic　drugs.　Therefore,　LND　may　be　very　promising　as　a　sensitizer　of　tumors　to　chemotherapeutic　agents　and　physical　therapies.　This　review　summarizes　the　advance　of　LND　in　combination　with　chemotherapy　and　physical　therapy　over　the　past　several　decades,　as　well　as　the　promising　LND　derivative　adjudin　(ADD).　The　underlying　sensitizing　mechanisms　were　also　analyzed　and　discussed,　which　may　contribute　to　an　improved　therapeutic　effect　in　future　clinical　cancer　treatment.　Lonidamine　(LND)　has　the　ability　to　resist　spermatogenesis　and　was　first　used　as　an　anti-spermatogenic　agent.　Later,　it　was　found　that　LND　has　a　degree　of　anticancer　activity.　Currently,　LND　is　known　to　target　energy　metabolism,　mainly　involving　the　inhibition　of　monocarboxylate　transporter　(MCT),　mitochondrial　pyruvate　carrier　(MPC),　respiratory　chain　complex　I/II,　mitochondrial　permeability　transition　(PT)　pore,　and　hexokinase　II　(HK-II).　However,　phase　II　clinical　studies　showed　that　LND　alone　had　a　weak　therapeutic　effect,　and　the　effect　was　short　and　reversible.　Interestingly,　LND　does　not　have　the　common　side　effects　of　traditional　chemotherapeutic　drugs,　such　as　alopecia　and　myelosuppression.　In　addition,　LND　has　selective　activity　toward　various　tumors,　and　its　toxic　and　side　effects　do　not　overlap　when　combined　with　other　chemotherapeutic　drugs.　Therefore,　LND　is　commonly　used　as　a　chemosensitizer　to　enhance　the　antitumor　effects　of　chemotherapeutic　drugs　based　on　its　disruption　of　energy　metabolism　relating　to　chemo-　or　radioresistance.　In　this　review,　we　summarized　the　combination　treatments　of　LND　with　several　typical　chemotherapeutic　drugs　and　several　common　physical　therapies,　such　as　radiotherapy　(RT),　hyperthermia　(HT),　and　photodynamic　therapy　(PDT),　and　discussed　the　underlying　mechanisms　of　action.　Meanwhile,　the　development　of　novel　formulations　of　LND　in　recent　years　and　the　research　progress　of　LND　derivative　adjudin　(ADD)　as　an　anticancer　drug　were　also　discussed.