Several ancient peoples all over the world have described reptilian beings, and some have described reptilian humanoids. Common in numerous mythologies are tales of reptilian creatures (usually not humanoid) who are often, but not always, hostile to human beings. Also rather common are the myths of "Serpents of Wisdom" who enlightened humanity before the dawn of civilization.

Some individuals, doubting claims of reptilian humanoid sightings or contacts, suggest that the mythological preeminence of reptilian forms could stem from a genetic memory of instincts developed millions of years ago, when mammals were the prey of the reptiles which dominated the Earth. Dreams of reptiles are often interpreted as symbolizing "ancient drives" and "instinctive responses".

One of many examples:
The Toltec Mayan god Gucumatz was described as a "serpent of wisdom" who enlightened humankind. His Aztec counterpart was named Quetzalcoatl. In the Yucatan, he is called Kukulcan.

The Hopi refer to a race of reptoids called the Sheti, or "Snake-Brothers", who live underground. The Cherokee and other Native American peoples also refer to reptoid races.

In pre-Columbian mythology from Colombia, Bachue (the primordial woman) transformed into a big snake. She is also sometimes called the "Celestial Snake" (Serpiente Celestial).

Many users of the drug Dimethyltryptamine (the active ingredient in many South American shamanic potions such as ayahuasca) have seen reptilian humanoids or reptilian disincarnate entities and aliens while hallucinating (Strassman 2000).