Consumption of fresh and fresh-cut fruits and vegetables is integral to a healthy diet. Unfortunately, outbreaks of human illness associated with the consumption of contaminated fresh produce continue to increase globally. Treatment of fresh produce with antimicrobial agents is a recommended practice to increase safety and shelf life. Many consumers are concerned with the potential health risks that may be associated with the more traditional antimicrobials and their by-products. Bacteriocins and chitosan have been extensively evaluated and exhibit good efficacy toward enhancing the microbial safety of fresh produce although challenges exist with their adoption. Newer technologies make it possible to improve delivery and efficacy of natural antimicrobials and other biocontrol agents. Using nanotechnology, coupling of natural antimicrobials is possible: nano- and microparticles composed of one natural antimicrobial containing another. Plant antimicrobial peptides are promising food antimicrobials due to their antibacterial and antifungal activities. An exciting new technology for decontamination of produce is photosensitization, which requires a photosensitizer, viable light, and oxygen. Products must be sprayed, drenched, or immersed in the photosensitizer to ensure direct contact with target microbes. Application of visible light in the presence of oxygen generates singlet oxygen capable of inactivating microbes. Application of natural antimicrobials preharvest and postharvest will be facilitated through the use of novel technologies. Challenges associated with availability, cost, consumer acceptance, and regulatory approval may limit the use of novel antimicrobials and treatments.