1. Tetrodotoxin (TTX) has been widely used as a chemical tool for blocking Na+ channels. However, reports are accumulating that some Na+ channels are resistant to TTX in various tissues and in different animal species. Studying the sensitivity of Na+ channels to TTX may provide us with an insight into the evolution of Na+ channels. 2. Na+ channels present in TTX-carrying animals such as pufferfish and some types of shellfish, frogs, salamanders, octopuses, etc., are resistant to TTX. 3. Denervation converts TTX-sensitive Na+ channels to TTX-resistant ones in skeletal muscle cells, i.e., reverting-back phenomenon. Also, undifferentiated skeletal muscle cells contain TTX-resistant Na+ channels. Cardiac muscle cells and some types of smooth muscle cells are considerably insensitive to TTX. 4. TTX-resistant Na+ channels have been found in cell bodies of many peripheral nervous system (PNS) neurons in both immature and mature animals. However, TTX-resistant Na+ channels have been reported in only a few types of central nervous system (CNS). Axons of PNS and CNS neurons are sensitive to TTX. However, some glial cells have TTX-resistant Na+ channels. 5. Properties of TTX-sensitive and TTX-resistant Na+ channels are different. Like Ca2+ channels, TTX-resistant Na+ channels can be blocked by inorganic (Co2+, Mn2+, Ni2+, Cd2+, Zn2+, La3+) and organic (D-600) Ca2+ channel blockers. Usually, TTX-resistant Na+ channels show smaller single-channel conductance, slower kinetics, and a more positive current-voltage relation than TTX-sensitive ones. 6. Molecular aspects of the TTX-resistant Na+ channel have been described. The structure of the channel has been revealed, and changing its amino acid(s) alters the sensitivity of the Na+ channel to TTX. 7. TTX-sensitive Na+ channels seem to be used preferentially in differentiated cells and in higher animals instead of TTX-resistant Na+ channels for rapid and effective processing of information. 8. Possible evolution courses for Na+ and Ca2+ channels are discussed with regard to ontogenesis and phylogenesis.