Purpose of Review <p>Bacteria are highly adaptive organisms that have evolved various survival strategies to persist and thrive in hostile environments. They especially form polymicrobial biofilms with an intricate microbial community network in a highly regulated fashion. This review covers recent findings on bacterial biofilm pathogenesis and innovative multidisciplinary therapeutic interventions for clinical infections.</p> Recent Findings <p>Bacterial cyclic dimeric guanosine monophosphate (cyclic di-GMP) is a central regulator for biofilm pathogenesis orchestrated by quorum sensing (QS) molecules, allowing prolonged survival, host immune evasion, antibiotic resistance, and augmented virulence with severe health consequences. Biofilms associated with medical devices or wounds pose significant risks due to sessile bacteria, which are notably more resistant to eradication than their planktonic counterparts due to diminished metabolic activities. This phenomenon complicates the treatment of biofilm-associated infections and exacerbates the persistence of chronic illnesses. Novel intervention strategies include CRISPR/Cas9, QS inhibitors, natural antimicrobial peptides, probiotics, antimicrobial nanomaterials, and advanced biophysical remedies.</p> Summary <p>A deeper understanding of the regulation of biofilm pathogenesis will facilitate the development of novel interventions suitable for clinical biofilms in various chronic infections.</p>