Hepatocellular　carcinoma　(HCC)　is　now　a　common　cause　of　cancer　death,　with　no　obvious　change　in　patient　survival　over　the　past　few　years.　Although　the　traditional　therapeutic　modalities　for　HCC　patients　mainly　involved　in　surgery,　chemotherapy,　and　radiotherapy,　which　have　achieved　admirable　achievements,　challenges　are　still　existed,　such　as　drug　resistance　and　toxicity.　The　emerging　gene　therapy　of　clustered　regularly　interspaced　short　palindromic　repeat/CRISPR-associated　nuclease　9-based　(CRISPR/Cas9),　as　an　alternative　to　traditional　treatment　methods,　has　attracted　considerable　attention　for　eradicating　resistant　malignant　tumors　and　regulating　multiple　crucial　events　of　target　gene-editing.　Recently,　advances　in　CRISPR/Cas9-based　anti-drugs　are　presented　at　the　intersection　of　science,　such　as　chemistry,　materials　science,　tumor　biology,　and　genetics.　In　this　review,　the　principle　as　well　as　statues　of　CRISPR/Cas9　technique　were　introduced　first　to　show　its　feasibility.　Additionally,　the　emphasis　was　placed　on　the　applications　of　CRISPR/Cas9　technology　in　therapeutic　HCC.　Further,　a　broad　overview　of　non-viral　delivery　systems　for　the　CRISPR/Cas9-based　anti-drugs　in　HCC　treatment　was　summarized　to　delineate　their　design,　action　mechanisms,　and　anticancer　applications.　Finally,　the　limitations　and　prospects　of　current　studies　were　also　discussed,　and　we　hope　to　provide　comprehensively　theoretical　basis　for　the　designing　of　anti-drugs.&　COPY;　2023　Published　by　Elsevier　B.V.　on　behalf　of　Shenyang　Pharmaceutical　University.　(　http://creativecommons.org/licenses/by-nc-nd/4.0/　)