As antibiotic resistance increases and antimicrobial options diminish, there is a pressing need to identify and develop new and/or alternative (non–antimicrobial-based) wound therapies. The authors describe the implications of antibiotic resistance on their current wound treatment paradigms and review the most promising non–antibiotic-based antimicrobial agents currently in research and development, with a focus on preclinical and human studies of therapeutic bacteriophages, antimicrobial peptides, cold plasma treatment, photodynamic therapy, honey, silver, and bioelectric dressings.