The period from 1607 to 1776 was characterized by almost constant conflict and compromise between colonists and Native peoples. What follows is a short list of very important conflicts with a brief description of each. Note that most of these conflicts could be traced essentially to disagreements over land and trade, but many also had their roots in Native American politics.

• Anglo-Powhatan Wars, 1609-1645: These were a series of conflicts between Virginia settlers and the powerful Algonquian confederacy under the leadership of Powhatan and later his brother Opechancanough. The result was the almost total destruction of Powhatan's power underneath the falls of the James River and the survival of Jamestown as a tobacco colony.
• Pequot War, 1637: This conflict, also fought over land incursions, culminated with a brutal massacre of Pequot people, mostly non-combatants, at a fort on the Mystic River. 
• King Philip's War, 1675-1676: New England colonists suspected Metacom, also known as "King Philip," of assembling a confederation of local Native peoples to attack. They launched a raid that led to some of the most violent fighting seen anywhere in the colonies. Eventually the colonists prevailed, crushing the once-powerful Narragansett tribe.
• Tuscarora/Yamassee Wars, 1711-1717: These conflicts were essentially a running war between coalitions of native peoples and the Carolinas (with their Indian allies. The causes were rooted in the Indian slave trade (especially the Yamassee War) and familiar disputes over land and trade. The South Carolina militia was instrumental in each, and shifting alliances among Indian peoples resulted in the defeat of first the Tuscarora, who moved to join the Iroquois Confederacy, and then the Yamassee, who were destroyed and sold into slavery.
• French and Indian Wars, 1754-1761: In these conflicts, the Algonquian people of the Ohio Valley as well as Canada largely sided with the French, while Iroquois people either stayed neutral or sided with the British and Anglo-American colonists. The war resulted in a British victory, which both permanently weakened the Ohio Valley Indians but also compromised the ability of the powerful Iroquois to "play off" the British and the French.
• American Revolution, 1776-1783: The American Revolution was an almost total disaster for Native peoples, who largely sided with the British. Most, in fact, like the Cherokee, were gripped by internal divisions over how to respond to the conflict. Even those peoples who did not side with Britain faced dispossession and removal in the aftermath of the war, and though many, most notably the Creek Confederacy, maintained considerable power in subsequent years, the American victory set in motion a chain of events that did not bode well for them.