The NFL will stage a minimum of two American football games a season over 10 years at Tottenham Hotspur's new stadium.
The 61,000-capacity venue - due to open in 2018 - will feature a retractable grass pitch with an artificial surface underneath for NFL games.
The stadium will be built adjacent to White Hart Lane - Spurs' current home.
Tottenham chairman Daniel Levy said the link-up with the NFL was a "compelling and exciting partnership".
What does the deal mean for Tottenham?
Tottenham will receive rent from the NFL - the world's richest sports league by revenue - for use of the stadium.
Spurs chairman Daniel Levy said the club "have an opportunity to deliver one of the most unique sports, leisure and entertainment venues in the world".
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But having reached a deal with the NFL, the north London club will need to meet a flexible stadium design complete with a pitch that disappears under the stands to reveal an artificial surface, and larger changing rooms as American football squads can exceed 60 players.
What do the NFL get out of it?
NFL commissioner Roger Goodell said his organisation "share a vision" with Tottenham, who are in discussions with the Football Association with the aim of playing at Wembley while the new stadium is being developed.
In using Tottenham's stadium as a regular venue, the NFL knows it has a pitch which can withstand several matches in a short period and that it has access to facilities its franchises are used to back in the US.
The move could also boost the chances of making London home to a permanent NFL franchise.
The National Football League is keen to grow its fan base in the UK and has been pleased with the way its 'International Series' fixtures at Wembley - played there since 2007 - have been received by fans.
All but one of those fixtures sold out and the Jacksonville Jaguars franchise agreed a deal with Wembley Stadium to play one fixture a season at the home of English football, between 2013 and 2016.
"I'm not sure this deal brings a London franchise closer in itself, but the more games we play the more fans we create and that's what takes the discussion over a franchise on another step," said David Tossell, Director of Public Affairs in Europe for the NFL.
What does it mean for Wembley?
Wembley Stadium was quick to issue a statement after Tottenham's announcement, stating "we look forward to the NFL remaining part of this iconic venue's annual schedule".
And the NFL is also intent on continuing to play matches at the venue, describing the arrangement with Spurs as "not exclusive".
"When the deal with Wembley Stadium is up in 2016, we fully expect to continue playing games there," added Tossell.
What does it mean for London?
Levy is keen for the new stadium to have a wide and positive impact on the London borough of Haringey and said the "hub" being built will create jobs.
The "hub" includes new homes, a hotel and tourist attractions.
Mayor of London Boris Johnson said: "Touchdowns in Tottenham can only add to our reputation as a global sporting powerhouse and help us take another step towards our goal of having a permanent NFL franchise in London."