The article discusses the challenges of treating microbial biofilms, which are a major cause of chronic infections. Biofilms are complex structures that protect bacteria from antibiotics and the host immune system. Current treatments are limited, and new strategies are needed to target biofilm structures and mechanisms of antibiotic resistance. The review highlights various therapeutic approaches, including physical methods like irrigation and debridement, surface coatings with antibiotics, and targeting the extracellular polymeric substance (EPS) matrix. It also discusses the use of EPS-targeting inhibitors, such as small molecules that block EPS production or degrade EPS, which can disrupt biofilms and enhance antibiotic effectiveness. Antibodies and nucleic acid-binding proteins are also explored as potential therapies. Additionally, the review covers the use of quorum sensing inhibitors to disrupt biofilm formation and dispersal. Other approaches include targeting dormant cells within biofilms, using metabolic inhibitors, and employing new technologies like nano-engineered materials and smart surfaces that respond to environmental cues. The review emphasizes the need for combination therapies and multi-targeted strategies to effectively treat biofilm infections, which are a significant challenge in clinical settings.The article discusses the challenges of treating microbial biofilms, which are a major cause of chronic infections. Biofilms are complex structures that protect bacteria from antibiotics and the host immune system. Current treatments are limited, and new strategies are needed to target biofilm structures and mechanisms of antibiotic resistance. The review highlights various therapeutic approaches, including physical methods like irrigation and debridement, surface coatings with antibiotics, and targeting the extracellular polymeric substance (EPS) matrix. It also discusses the use of EPS-targeting inhibitors, such as small molecules that block EPS production or degrade EPS, which can disrupt biofilms and enhance antibiotic effectiveness. Antibodies and nucleic acid-binding proteins are also explored as potential therapies. Additionally, the review covers the use of quorum sensing inhibitors to disrupt biofilm formation and dispersal. Other approaches include targeting dormant cells within biofilms, using metabolic inhibitors, and employing new technologies like nano-engineered materials and smart surfaces that respond to environmental cues. The review emphasizes the need for combination therapies and multi-targeted strategies to effectively treat biofilm infections, which are a significant challenge in clinical settings.