From about 1000 BC to AD 1450, eastern North America witnessed the rise and fall of three distinctive prehistoric cultures known as the Adena, Hopewell - both named after the find-sites - and the Mississippian. Each culture was characterized by the building of mounds. The eastern woodlands, a zone that was centered in Ohio and which extends into Pennsylvania, West Virginia, Kentucky, and Indiana, was the birthplace of the Adena culture.

Between 1000 BC and 300 BC, the Adena people constructed large scale earthen monuments, some of which, known as effigy mounds, are in the shape of living creatures. More frequently, the earthworks form enclosures, many perfectly circular, consisting of a low embankment with a parallel internal ditch. These "sacred circles" are thought to have been used for ceremonies, and some enclose burial mounds. Inside the burial mounds are the remains of people who merited elaborate funerary rites. The rich burials and political organization required to build the sacred circles indicate that Adena was a chiefly society.

Hopewell culture (300 BC-AD 500) can be seen as a continuation and elaboration of basic patterns established in Adena times. Hopewell earthworks were large and sometimes built in complexes, where circular, rectangular and polygonal enclosures were linked by long, embankment-edged causeways. Burial mounds were built inside or near the enclosures and covered multiroomed log tombs. Several rooms were needed: one for the important first burial; another to contain subsequent interments of cremated human bones; and a third for the very large quantities of grave goods which included flint and obsidian dart tips, spearthrowers, stone knives and polished axes.

Hopewell-derived cultures covered North America from western New York to Kansas and from the Gulf of Mexico to Lake Huron. Their trading contacts extended even farther, proved by finds in burial mounds. Conch shells from the Gulf coast have been found in Wisconsin and Michigan; shark's teeth in Illinois, obsidian and grizzly bear teeth from the far west in Illinois and Ohio.

The Mississippian culture, which extended from the Atlantic coast to Oklahoma and from Minnesota to Mississippi, first became predominant in the Middle Mississippi Valley from about AD 700. It was characterized by rectangular flat-topped mounds which formed platforms for timber temples, mortuary houses and chiefly residences. About 20 mounds, grouped around a plaza and encircled by a stout pallisade fence, formed the center of the oldest towns known in North America. Urban centers, such as Cohokia, housed populations of up to 10,000; and rural zones contained permament villages with dense populations supported by intensive maize cultivation.

Many Mississippian burials contain valuables, including copper and mica sheet ornaments, pearls, monolithic stone axes, pottery vessels in the form of trophy heads, and shell vessels. They are decorated with incised motifs, such as weeping eyes, flying winged human figures, and sunburst designs that relate to a religion known as the Southern Cult. Mississippian culture peaked in about AD 1250, then declined until, by AD 1450, the Middle Mississippi had become a depopulated area. The densely packed town dwellers had fallen victim to epidemic disease, a fate which was to befall many of their fellow Americans, who had no defense against the illnesses brought by Europeans.