Dental　caries　is　one　of　the　most　prevalent　and　costly　biofilm-associated　infectious　diseases　worldwide.　Streptococcus　mutans　(S.　mutans)　is　well　recognized　as　the　major　causative　factor　of　dental　caries　due　to　its　acidogenicity,　aciduricity　and　extracellular　polymeric　substances　(EPSs)　synthesis　ability.　The　EPSs　have　been　considered　as　a　virulent　factor　of　cariogenic　biofilm,　which　enhance　biofilms　resistance　to　antimicrobial　agents　and　virulence　compared　with　planktonic　bacterial　cells.　The　traditional　anti-caries　therapies,　such　as　chlorhexidine　and　antibiotics　are　characterized　by　side-effects　and　drug　resistance.　With　the　development　of　computer　technology,　several　novel　approaches　are　being　used　to　synthesize　or　discover　antimicrobial　agents.　In　this　mini　review,　we　summarized　the　novel　antimicrobial　agents　targeting　the　S.　mutans　biofilms　discovery　through　computer　technology.　Drug　repurposing　of　small　molecules　expands　the　original　medical　indications　and　lowers　drug　development　costs　and　risks.　The　computer-aided　drug　design　(CADD)　has　been　used　for　identifying　compounds　with　optimal　interactions　with　the　target　via　silico　screening　and　computational　methods.　The　synthetic　antimicrobial　peptides　(AMPs)　based　on　the　rational　design,　computational　design　or　high-throughput　screening　have　shown　increased　selectivity　for　both　single-　and　multi-species　biofilms.　These　methods　provide　potential　therapeutic　agents　to　promote　targeted　control　of　the　oral　microbial　biofilms　in　the　near　future.　Copyright　©　2022　Zhang,　Zhao,　Tian,　Lei　and　Huang.