The 16th 'International series' game in London is another ground-breaking moment in front of a 75,000 sell-out crowd
Just nine years after Eli Manning headlined the NFL's first tentative steps into uncharted territory, the New York Giants star returns to England with his sport now firmly established as a global force.
Manning, the Giants' Superbowl-winning quarterback, is one of his team's few remaining players from the group that defeated the Miami Dolphins at Wembley in the first NFL regular-season game to be played in the United Kingdom.
On Sunday, Manning will be part of another historic occasion at Twickenham when the Giants face the Los Angeles Rams in the first NFL fixture to be staged at the 107-year-old home of rugby union.
That the 16th 'International series' game in London is another ground-breaking moment in front of a 75,000 sell-out crowd underscores how much the NFL's appeal has grown overseas since that initial venture in 2007.
Back then, even NFL chiefs were uncertain if their gamble would pay off and a negative response from a country obsessed with soccer could have sunk the plan at the first attempt.
Playing on foreign turf was such an alien concept for the NFL that some Giants players didn't even know what country they were in when they touched down in England.
"I just remember guys were in a daze a little. They didn't know where they were or what was going on, what country they were in," Manning recalled this week.
"(Giants running back) Brandon Jacobs wanted to go see the Eiffel Tower!"
Despite the reluctance of Manning's fellow travellers, 81,000 fans packed Wembley to see the first match and the NFL has ramped up its presence since then with no signs of the public losing interest.
"It's been a while since I last went over there. But I had a great experience the first time. I'm excited to go back," Manning said.
This is the third successive year that three games will be played in London and the Jacksonville Jaguars are playing one 'home' match at Wembley each season from 2013 to 2020.
Not content with UK dominance, the NFL are playing a fixture in Mexico in November and commissioner Roger Goodell is on record as saying he wants to take a regular-season game to China in the near feature, with Germany and Brazil also potential venues.
A 10-year deal has been signed with Premier League club Tottenham to play two matches per year from 2018 at their redeveloped White Hart Lane stadium.
The NFL would love to install a full-time franchise in the UK and Tottenham chairman Daniel Levy has suggested his club would be the ideal hosts of a permanent team.
With 14 million British fans and viewership of Sunday games on television more than doubling since 2007, the NFL's target of having a UK team by 2022 remains well within reach according to Mark Waller, the league's British-born executive vice-chairman of international.
"The fan base is big enough and passionate enough that it can support a franchise," Waller said.
"I felt in 2007 it was always a 15-year journey. I think we're on track to deliver that. I fundamentally believe we will deliver that."
Rams head coach Jeff Fisher has just experienced the pros and cons of setting up home in a new city after his team moved from St Louis to Los Angeles in the summer.
Fisher has no doubts the UK is ready for its own team and he believes it would prove a huge success.
"The enthusiasm, the support is clearly here. There's no doubt about that. I know the league is looking really hard at it," Fisher said.
"It would be great for the NFL if that were able to happen."