As the consumption of seafood and shellfish increases around the world, so is the incidence of associated outbreaks of illness. Various postharvest treatments are effective at killing seafood-associated bacteria, but most of these treatments also kill the mollusks. Because consumer preferences for raw live shellfish persist, biological approaches for promoting microbiological safety of live product are being considered. Applications of probiotic bacteria to reduce human pathogens in live shellfish could augment current practices for preharvest monitoring of water quality. Postharvest, biological controls will be important to remove shellfish-associated commensal Vibrio spp. that are pathogenic to humans. Further investigations will reveal whether combining depuration with chemical disruption of bacterial attachment or cell-to-cell signaling may accomplish this goal.