Premier League heavyweights such as Manchester United and Arsenal enter the competition on Tuesday as the third round of the Carling Cup gets underway.
Those teams involved in Europe were give a bye in the previous round and begin their campaigns at the last 32 stage as they aim to reach the Wembley showpiece next February.
There are ten ties on Tuesday and, while many of the top-flight teams will take the opportunity to rest players, they will also be determined to avoid becoming victims of a giant-killing.
Manchester United famously lost to Leeds in the FA Cup a couple of seasons ago and now have the chance to avenge that defeat when they travel to Elland Road, in a match that can be seen live on Sky Sports HD2.
United have been unstoppable in the Premier League since the start of the season and Sir Alex Ferguson will be confident of marching on with another victory in Yorkshire, although his team will have a different look to it with the likes of Michael Owen and Paul Pogba set to start.
A dismal few months for Arsenal can be traced back to their Carling Cup final heartbreak last term at the hands of Birmingham and, with confidence so low, Arsene Wenger may not be relishing a clash with League Two high-flyers Shrewsbury at Emirates Stadium.
Stoke and Tottenham also start their Carling Cup adventures this week in an all-Premier League encounter, on the back of contrasting weekend results.
Another battle between two Premier League protagonists sees unbeaten Aston Villa, whose manager Alex McLeish lifted the trophy last season with Birmingham, go up against out-of-form Bolton.
Newcastle have made a fine start to the season and may fancy their chances of going a long way in the competition, but first they must overcome a Nottingham Forest side that has struggled so far under Steve McClaren and will be desperate for a kick-start.
The pressure was lifted on Steve Kean on Saturday following a thrilling victory over Arsenal and Blackburn will be hoping to carry on the feel-good factor against League One strugglers Leyton Orient, whose only victories this season have come in the Carling Cup.
Wolves' fine form has unravelled somewhat with back-to-back defeats and Mick McCarthy's men will be aiming to get back on track when Championship outfit Millwall visit Molinuex.
Middlesbrough lock horns with Crystal Palace at Selhurst Park for the second time in the space of four days after seeing off the Eagles 1-0 over the weekend to maintain their unbeaten start to the season.
Elsewhere on Tuesday, Burnley entertain Milton Keynes Dons at Turf Moor, while Aldershot of League Two can spring a minor surprise by knocking out third-tier Rochdale.