With the Premier League and Championship sides now entering the competition, it's when things could get interesting - the competition is known for higher-league sides losing against teams below them in the pyramid.
Which fixtures look like the ones most likely to throw up a giant-killing? Here are 5 picks by Football Manics, looking exclusively at games between teams more than one division apart.
Bournemouth (Premier League) vs. Wigan Athletic (League One)
Bournemouth have won just one of their last 11 matches in all competitions and have conceded 14 goals in their last five Premier League games, leaving them flirting with relegation.
In addition, Eddie Howe's side have a hefty absence list, with a number of changes likely to be made, and their recent FA Cup pedigree isn't great, having crashed out to Millwall in the third round last year.
Wigan, meanwhile, are top of League One, have scored 50 goals and are unbeaten in 10 in all competitions, so they stand a good chance of upsetting their opponents at the Vitality Stadium.
Brentford (Championship) vs. Notts County (League 2)
Although Brentford are doing well in the Championship, sitting 11th and with three wins and a draw from their last six, they come into this game on the back of a heavy defeat to Wolves.
County, managed by former Premier League stalwart Kevin Nolan, are a different beast to the meek outfit of seasons gone past, sitting pretty in the League Two automatic promotion slots.
Magpies striker Jon Stead was part of the Bradford City team that upset Chelsea a few years ago and his experience and wisdom, combined with the talent and grit of the team - which has already beaten higher-league opposition in Bristol Rovers - makes them dangerous.
Exeter City (L2) vs. West Bromwich Albion (PL)
Exeter have slipped off the boil in recent weeks, going from the League Two automatic promotion places to seventh, but they're a tough proposition at home, with seven wins from their last 10 league games.
The problem is more with West Brom having gone so long without a win, and Alan Pardew having failed to provide a turnaround as he seeks victory at the ninth time of asking.
Can West Brom get their season back on track or will the Grecians dish out another miserable afternoon, adding to what has been a dreadful season for the Baggies? I can see the hosts potentially getting a draw.
Coventry City (L2) vs. Stoke City (PL)
Coventry famously won the trophy back in the 80s and, despite their fall from grace culminating in a spot in the fourth tier this season, they've done well so far, sitting third in the table, and with four wins from their five festive games, plus a solid home record.
Stoke, meanwhile, are having a woeful season, having slipped into the bottom three, Mark Hughes is believed to be on thin ice in terms of his spell at the club, and the Potters are in the midst of a defensive crisis, with Ryan Shawcross, Bruno Martins Indi and Erik Pieters out injured.
Perhaps an outright win might be a bridge too far for Coventry, but a replay is certainly a possibility.
Newcastle United (PL) vs. Luton Town (L2)
On the whole, Newcastle's recent FA Cup pedigree is not great - they were knocked out of the FA Cup by League One side Oxford last season and have lost five of their last six ties against lower league opposition in this competition.
The Magpies' good early-season has given way to a tumble down the table in recent months to leave them nervously looking over their shoulder, even though two wins and a draw in the last four have stopped the rot.
The question is, how seriously will they take the cup given their fight against relegation? Considering they're taking on a side top of League Two and boasting a goal difference of +37, the likelihood of an upset is certainly not low.