Southwestern cultures included about a quarter of all native North Americans. These descendants of the Mogollon, Hohokam, and Anasazi cultures lived in settled agricultural communities, many of them pueblos. They continued to grow corn, beans, and squash using methods they had refined for centuries.

However, their communities came under attack by a large number of warlike Athapascans who invaded the Southwest beginning around AD 1300. The Athapascans—principally Apache and Navajo—were skillful warriors who preyed on the sedentary Pueblo Indians, reaping the fruits of agriculture without the work of farming.

About a fifth of all native North Americans resided along the Pacific coast. In California, abundant acorns and nutritious marine life continued to support high population densities, but this abundance retarded the development of agriculture. Similar dependence on hunting and gathering persisted along the Northwest coast, where fishing reigned supreme. Salmon were so plentiful at The Dalles, a prime fishing site on the Columbia River on the border of present-day Oregon and Washington, that Northwest peoples caught enough to use themselves as well as to trade dried fish as far away as California and the Great Plains. It is likely that The Dalles was the largest Native American trading center in ancient North America, although other ancient trading centers, such as Pueblo Bonito and Cahokia, also existed.