The two sides have plenty of history but the rivalry has turned ugly in recent seasons, making Sunday a must-watch encounter.
In just the second weekend of the season, one of the juiciest match-ups of the season gets underway Sunday with England's most historic stadium as the setting.
A 2-0 win over Newcastle United on the opening weekend saw Tottenham begin the new campaign in similar form to last season, efficient and clinical.
Against Chelsea, they'll face a tougher test and could be without both first choice full-backs. Danny Rose is out for Sunday's London derby with his knee injury, while Kieran Trippier faces a late fitness test for his ankle injury.
Georges-Kevin N'Koudou and Erik Lamela have also been ruled out with both still a couple of weeks away from a return. A win on Sunday for Tottenham would be monumental, with a victory over a title rival coming so early in the season.
The disappointment of Wembley last season can also begin to turnaround with the historic stadium posing as their home for the next couple of years.
Likely XI: Lloris; Walker-Peters, Alderweireld, Vertonghen, Davies; Dier, Wanyama; Eriksen, Alli, Son; Kane.
Antonio Conte's Chelsea were already short on midfielders before Cesc Fabregas' red card last weekend. The Spanish midfielder will miss through suspension, as will captain Gary Cahill who also saw red against Burnley.
A 3-2 defeat to Burnley on the opening weekend was the last thing Blues fans wanted to see after a disappointing summer.
There is good news on the Chelsea front as Eden Hazard and Tiemoue Bakayoko may be in line to appear against Tottenham. Late fitness tests are expected for the duo, with the latter being much more likely to feature.
Victor Moses and Pedro are also set to return for Chelsea; the former returning from a suspension while the latter seems to have recovered from an ankle injury.
A defeat on Sunday would give Chelsea fans haunting memories of their disastrous 2015-16 campaign, making Sunday's London derby all the more important.
Likely XI: Courtois; Christensen, Azpilicueta, David Luiz; Moses, Bakayoko, Kante, Alonso; Boga, Willian, Morata.
Chelsea won the last outing between the two London sides, an FA Cup semi-final at Wembley. The Blues will aim to continue their strong record over Tottenham at Wembley.
The two Premier League meetings were split last season as the home side won each fixture. The London rivals also finished next to each other in the league table as Chelsea were crowned Premier League champions, while Tottenham finished a close second.
Sunday's match will mark the first ever Premier League meeting between the two at Wembley, as well as Tottenham's first official league game at the national stadium, though they played their Champions League home games there last season.