League One high-fliers Swindon, Yeovil, Stevenage and Tranmere go in search of Premier League scalps in the second round of the Capital One Cup on Tuesday.
Crewe, Scunthorpe and Walsall will also be representing the third tier against top-flight opposition, while League Two hopefuls Morecambe entertain Sunderland and Nottingham Forest play host to Wigan in front of the Sky Sports cameras.
Yeovil sit proudly atop of the League One standings three games into the new season and will believe that they can cause West Brom plenty of problems at Huish Park.
Swindon are a side with momentum firmly behind them and a trip to Stoke should hold no fear for Paolo Di Canio's men.
Stevenage have a made a bright start to the 2012/13 campaign and will be looking forward to pitting their wits against a Southampton team still finding their feet in the Premier League.
Tranmere are the fourth side in the third tier sat on seven points and will be looking to inflict a third straight defeat on Paul Lambert's Aston Villa.
Scunthorpe saw off Derby in a first round classic and will be hoping for more heroics when they go to Norwich.
Walsall and Crewe will both head out on the road in midweek, with ties against top-flight duo Queens Park Rangers and West Ham awaiting them.
Sunderland could hand debuts to big-money arrivals Steven Fletcher and Adam Johnson when they host Morecambe.
The other fourth-tier outfits in action on Tuesday are Plymouth, Burton, Oxford and Bradford, who travel to Burnley, Leicester, Leeds and Watford respectively.
Swansea are enjoying life under new boss Michael Laudrup and will be looking to continue their impressive form in front of goal when they welcome Barnsley to South Wales.
Fulham face a tough trip to Sheffield Wednesday, who have settled quickly back in the Championship, while Reading go in search of their first win of the season in a home date with Peterborough.
There is a Midlands derby at the Ricoh Arena as Coventry take on Birmingham and Yorkshire pride is put on the line at the Keepmoat Stadium as Doncaster face Hull City.
Crystal Palace make the long journey north to face Preston at Deepdale, Ipswich have even further to travel as they visit Carlisle and Middlesbrough head south to Gillingham.
MK Dons tackle a Blackburn side that have made an unbeaten start to the season, while Bolton will be looking for a morale-boosting success at Crawley.
The final fixture on a busy night of knockout competitions sees Nottingham Forest face Wigan at the City Ground in a game which can be seen live on Sky Sports 2 HD.