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Massachusett Tribe inhabited the area that would become Cambridge for thousands of years prior to European colonization of the Americas, most recently under the name Anmoughcawgen. At the time of European contact and exploration, the area was inhabited by Naumkeag or Pawtucket to the north and Massachusett to the south, and may have been inhabited by other groups such as the Totant not well described in later European narratives. The contact period introduced a number of European infectious diseases which would decimate native populations in virgin soil epidemics, leaving the area uncontested upon the arrival of large groups of English settlers in 1630.

In December 1630, the site of present-day Cambridge was chosen for settlement because it was safely upriver from Boston Harbor, making it easily defensible from attacks by enemy ships. The city was founded by Thomas Dudley, his daughter Anne Bradstreet, and his son-in-law Simon Bradstreet. The first houses were built in the spring of 1631. The settlement was initially referred to as “the newe towne”. Official Massachusetts records show the name rendered as Newe Towne by 1632, and as Newtowne by 1638.

Located at the first convenient Charles River crossing west of Boston, Newtowne was one of several towns, including Boston, Dorchester, Watertown, and Weymouth, founded by the 700 original Puritan colonists of the Massachusetts Bay Colony under Governor John Winthrop. Its first preacher was Thomas Hooker, who led many of its original inhabitants west in 1636 to found Hartford and the Connecticut Colony; before leaving, they sold their plots to more recent immigrants from England. The original village site is now within Harvard Square. The marketplace where farmers sold crops from surrounding towns at the edge of a salt marsh (since filled) remains within a small park at the corner of John F. Kennedy and Winthrop Streets.