The west Londoners have never won away to their capital rival and Rene Meulensteen's men, who have leaked goals since his appointment, face a stern test against the league leader.
The two London clubs first met in an FA Cup tie in 1904, when Arsenal's 3-2 victory set the tone for future meetings.
In the 26 fixtures at Arsenal since then, Fulham has never won, suffering 21 defeats along the way.
The task awaiting the club this weekend is no less daunting than usual, with Arsene Wenger's side sitting top of the Premier League, unbeaten at home in the league since the opening day.
Fulham let in six in its last away league match, when the team was hammered at Hull City, although the Premier League win over West Ham and FA Cup triumph versus Norwich City has since lifted the spirits of Rene Meulensteen's men, who head across the capital one point and two places above the relegation zone.
The Dutch coach was boosted by the long-awaited return of defender Brede Hangeland in Tuesday's 3-0 FA Cup third-round replay win over Norwich.
The Norway international had been out since October with a sciatic nerve problem, but helped the side to a first clean sheet in eight matches.
Arsenal has had injury problems to contend with, too, and Theo Walcott, who has undergone surgery on his anterior cruciate knee ligament, will not play again this season.
Walcott joins the likes of Mikel Arteta (calf), Nicklas Bendtner (ankle), Aaron Ramsey (thigh) and Thomas Vermaelen on the sidelines.
Midfielder Tomas Rosicky had an operation on his broken nose and may play with the aid of a mask, while Nacho Monreal (foot) is, in the words of Wenger, "a big doubt".
Arsenal was a 3-1 winner at Craven Cottage in August and this will be the club's 200th London derby in the Premier League.