This review focuses on the challenges and current therapeutic strategies for targeting microbial biofilms, which are a significant cause of chronic infections. Biofilms are complex microbial communities that exhibit enhanced resistance to antimicrobial agents due to their structural and functional traits, such as the extracellular matrix (ECM) and dormant cells. The review highlights the need for multi-targeted or combinatorial therapies to overcome the limitations of conventional antimicrobials. It discusses emerging technologies and strategies, including the targeting of the ECM, dormancy, and quorum sensing (QS) systems. The role of surface modifications, such as nanostructured surfaces and antimicrobial coatings, in preventing and disrupting biofilms is also explored. Additionally, the review examines the potential of antimicrobial peptides (AMPs) and their combination with other therapeutic approaches to enhance efficacy. Despite the progress, challenges remain in translating these strategies into clinical practice, particularly in addressing the complexity of biofilm microenvironments and the development of resistance. The review emphasizes the importance of multi-targeted therapies and the need for further research to improve the efficacy and safety of biofilm-targeting treatments.This review focuses on the challenges and current therapeutic strategies for targeting microbial biofilms, which are a significant cause of chronic infections. Biofilms are complex microbial communities that exhibit enhanced resistance to antimicrobial agents due to their structural and functional traits, such as the extracellular matrix (ECM) and dormant cells. The review highlights the need for multi-targeted or combinatorial therapies to overcome the limitations of conventional antimicrobials. It discusses emerging technologies and strategies, including the targeting of the ECM, dormancy, and quorum sensing (QS) systems. The role of surface modifications, such as nanostructured surfaces and antimicrobial coatings, in preventing and disrupting biofilms is also explored. Additionally, the review examines the potential of antimicrobial peptides (AMPs) and their combination with other therapeutic approaches to enhance efficacy. Despite the progress, challenges remain in translating these strategies into clinical practice, particularly in addressing the complexity of biofilm microenvironments and the development of resistance. The review emphasizes the importance of multi-targeted therapies and the need for further research to improve the efficacy and safety of biofilm-targeting treatments.