Free fatty acids (FFAs) have long been acknowledged for their antimicrobial activity. More recently, long-chain FFAs (>12 carbon atoms) are receiving increased attention for their potent antivirulence activity against pathogenic bacteria. In the gastrointestinal tract, foodborne pathogens encounter a variety of long-chain FFAs derived from the diet, metabolic activities of the gut microbiota, or the host. This review highlights the role of long-chain FFAs as signaling molecules acting to inhibit the infectious potential of important foodborne pathogens, including Salmonella and Listeria monocytogenes. Various long-chain FFAs interact with sensory proteins and transcriptional regulators controlling the expression of infection-relevant genes. Consequently, long-chain FFAs may act to disarm bacterial pathogens of their virulence factors. Understanding how foodborne pathogens sense and respond to long-chain FFAs may enable the design of new anti-infective approaches.