1640: Lake Erie discovered by Europeans - exact date of discovery by First Nations unknown.
1640: Françoise Marie Jacqueline, youthful daughter of a physician from Nogent, France, sets sail for what would become Saint John, New Brunswick, to wed Charles de Saint-Étienne de La Tour, Governor of Acadia, and to assume many roles, including wife, confidant, soldier and businesswoman. In spite of the ongoing and escalating conflict between LaTour and his well-connected rival Governor, Charles de Menou, Sieur d'Aulnay, she would elevate LaTour's status amongst the power brokers of the day in France and in the growing English colonies to the south. In 1645, she would successfully defend Fort LaTour against a vicious attack by d'Aulnay, only to be betrayed, ultimately losing her life. Buried in the vicinity of the Fort, in what is now downtown Saint John, her bones have never been found. Remains of the Fort still exist, protected as a national heritage site, hidden beneath layers of ancient soil.
1644: Second Powhatan Confederacy uprising against Jamestown, Virginia; its leader, Opechancanough, dies in captivity.
1644 Jeanne Mance (Baptized Langres, France November 12, 1606 Died June 18, 1673) opens Hotel-Dieu, the first hospital in North America.
1645-63: Under the proprietorship of Richelieu's company's colonial agent, the Community of Habitants, the new French colony takes shape along the St. Lawrence.
1648-49: After the Iroquois brutally ravage Huron country and disperse the Huron nation north of the St. Lawrence, they turn against New France itself.
1649-64: the Beaver Wars: Encouraged by the English, and the need for more beaver for trade (their own area being hunted out), Haudenosee (Iroquois) make war on Hurons (1649), Tobaccos (1649), Neutrals (1650–51), Erie (1653–56), Ottawa (1660), Illinois and Miami (1680–84), and members of the Mahican confederation. English, pleased with this, agree to 2-Row Wampum Peace treaty, 1680.
1649: Attacks by the Iroquois disperse the Huron; disrupts fur trade over the next fifteen years.