Manchester United, Newcastle, Arsenal, Tottenham and Liverpool all begin their Capital One Cup campaigns on Wednesday evening.
Ten teams are already through to the next round and the draw for the last 16 will be made after the completion of the midweek action.
The big clash of the night pits together two teams who won in the Premier League at the weekend as Manchester United entertain Newcastle United at Old Trafford, with Darren Fletcher set to make his first start in ten months for the home side.
Arsenal have made an impressive start to the season and will be determined to keep that run going in an effort to claim some silverware after seven barren years, with Coventry City facing the daunting task of trying to cause an upset at Emirates Stadium.
Carlisle United are another League One side looking to claim the scalp of a top-flight giant and have home advantage against Tottenham Hotspur, who have started to raise their game in recent weeks.
Defending League Cup champions Liverpool have the chance to exact revenge on West Bromwich Albion for their Premier League defeat on the opening day of the campaign when they return to The Hawthorns, although it will not be easy against Steve Clarke's in-form Baggies.
There is another all Premier League affair at Loftus Road, where the Capital One Cup is sure to provide a welcome distraction for the bottom two clubs as Queens Park Rangers tackle Reading.
Norwich City have also struggled so far in the league but they did manage to beat Scunthorpe in the previous round and will be keen to progress in the competition by seeing off Doncaster Rovers.