Tetrodotoxin (TTX) is one of the most potent and oldest known neurotoxins. The poisoning cases due to ingestion of TTX-containing marine animals, especially for puffer, have frequently occurred in Asia since a long time ago. This chapter describes various topics on TTX poisoning including the tendency of poisoning incidents, typical case report, treatment and prevention, biology distribution, original source, infestation mechanism, detection methods, characteristics of chemistry and pharmacology, and therapeutic application. Furthermore, the protocols for how to make puffer safe to eat and how to prevent puffer products made from toxic puffers have been suggested. Finally, the biological significance and neurophysiological role of TTX have been elucidated and TTX may act as an important drug like anesthetic in future.