The Gunners - fresh from beating Barcelona 2-1 on Wednesday - continue their four-pronged assault on silverware with a trip to Leyton Orient, a midtable team in England's third tier.
Arsenal manager Arsene Wenger is set to rest his key players ahead of a busy month for the London club but will be wary of Orient, which has defeated two leading second-division teams away from home en route to the last 16.
"There will be some rotation. We will see what I do. We play Sunday, Wednesday and then Sunday again but I have shown in many competitions that I have the same belief in every player," Wenger said.
"This competition is very different (to the Champions League). In England, you have to be focused for these kind of things."
Orient, which saw off Norwich and Swansea in the last two rounds, has been in the news in recent weeks for off-the-field reasons.
West Ham's prospective move to the Olympic Stadium after the London Games in 2012 could put the future of the Os at risk, with the 130-year-old club's Brisbane Road ground situated close to the showpiece venue.
Orient fears it will lose fans because West Ham could offer free and heavily discounted tickets to spectators, so a televised match against Arsenal is the perfect opportunity for fans to vent their feelings in front of a national audience.
Wenger should have Theo Walcott available despite the winger hurting his hamstring against Barcelona and right back Bacary Sagna is back from suspension, but Switzerland center back Johan Djourou is out with a back injury.
Non-league side Crawley Town visits Premier League leader Manchester United in what should be an even bigger mismatch.
Crawley is 93 places below United in the league ladder but is promising to make a game of it at Old Trafford.
"I think that we are genuinely one of the teams that could possibly get a positive result there," manager Steve Evans said. "It will just be Manchester United vs. Crawley Town, and as far-fetched as that sounds, that's what it is.
"The fact that (United coaches) Sir Alex (Ferguson) and Mike Phelan came to our match on Tuesday against Wrexham maybe tells us they are treating it a bit more seriously than many people thought."
Ferguson said United, which has won the FA Cup a record 11 times, will field its reserve-team players on Saturday, meaning the likes of Wayne Rooney and Ryan Giggs will be rested.
"We respect the fact that Crawley are the best non-league side for quite a while. They're very committed and aggressive and it'll be a tough game," Ferguson said.
"They talk about the FA Cup dying but it won't die as long as you've got giant-killing acts that Crawley have already produced."
Other last-16 matches see Fulham host Bolton on Sunday and Premier League struggler West Ham at home to Burnley on Monday. Bolton discovered on Friday it will be without defender Sam Ricketts for the rest of the season after he was diagnosed with a ruptured Achilles' tendon,
Third-tier teams Brighton and Sheffield Wednesday visit Stoke and Birmingham respectively on Saturday.
The two remaining fourth-round replays are also being played this weekend.
Defending champion Chelsea hosts Everton in an all-Premier League match and Manchester City is at home to third-tier Notts County, with Aston Villa awaiting the winner.
Arsenal faces London derby in 5th round of FA Cup
Advertisement