Tetrodotoxin (TTX), which was named after the puffer family Tetraodontidae, was first isolated from pufferfish in the 1950s. The structure of TTX was determined in 1964, since then TTX studies have attracted wide attentions from biologists, toxicologists, chemists and pharmacologists. TTX and many of its naturally-occurring analogues have been found in a range of marine organisms and in a few amphibians. It has been suggested that TTX and its analogues probably play a role in defense, predation or communication, and the tissue distribution of the toxins in TTX-bearing animals is highly relevant to its potential ecological roles. TTX-bearing animals show high resistance to TTX and its analogues, which is possibly due to the presence in these animals of TTX-binding proteins or uniquely-structured sodium-ion channels. This article reviews recent advances in the studies on the ecological roles of TTX, the resistance mechanisms of TTX-bearing organisms, and the prevention of TTX-poisoning.