Medical biofilms are a significant problem in chronic diseases like diabetic ulcers that do not heal, infections of medical devices and CF. The extracellular polymeric matrix is a barrier to antibiotic penetration. In search of an alternative, approaches based on antimicrobial peptides (AMPs) and enzymes have been developed to tackle the multi-drug resistance. This review collates the existing literature on zoonotic and bacterial origin AMPs, along with the matrix-disrupting and quorum-quenching enzymes, highlighting those which have proven to be effective / against clinical isolates from patients. Enzymes (e.g. cellulase, alginate lyase, and dispersin B) can break down matrix components or block critical signaling molecules and can be seen to have strong synergy with antibiotics, whereas AMPs disrupt cell membranes and downregulate genes that encode biofilm-forming proteins. Our analysis reveals however, a key translational bottleneck: there were no clinical trials in human subjects identified despite strong preclinical evidence of activity. This review discusses these encouraging pre-clinical findings and identifies specific physiological and challenges that need to be overcome to take these alternative therapies to clinical practice.