The world of food safety is a complex tapestry, woven together by various contaminants and hazards that can compromise consumer well-being. Among these, tetrodotoxin (TTX) stands out as a potent and potentially lethal neurotoxin found in certain marine creatures, notably the pufferfish. TTX presents a formidable challenge in food safety due to its minuscule lethal dose and paralyzing effects. This chapter explores TTX’s origins, toxicology, distribution, and mitigation measures. Contrary to popular belief, TTX is produced by marine bacteria, which can transfer their TTX-producing genes to marine hosts, such as pufferfish. TTX exerts its effects by blocking voltage-gated sodium channels, leading to rapid onset of symptoms including paralysis. The occurrence and distribution of TTX in marine organisms and the complexities of its ecological dynamics are examined, highlighting the need for vigilant monitoring and assessment of seafood safety. Furthermore, TTX’s heat stability and lack of taste or odor complicate its detection in food. Reliable detection methods, including LC-MS and ELISA, are essential for assessing and mitigating risks associated with TTX. The chapter underscores the importance of stringent regulations, public education, and international collaboration to ensure food safety and prevent TTX-related poisoning incidents.