Southgate dropped captain Wayne Rooney for the international break, with the newly-appointed manager making some tough calls ahead of Wednesday's friendly against Germany in Dortmund.
Theo Walcott was a surprise omission as Southgate shapes his squad with an emphasis on youth - Jermain Defoe's recall aside - and Southgate needs his faith in younger members of his squad to be repaid on the road to Russia 2018.
England currently lead Group F with three wins and a draw from their opening four matches, but failure to beat Edgaras Jankauskas's Lithuania this weekend could cost them top spot.
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England host Lithuania at Wembley Stadium on Sunday, March 26, with kick-off scheduled for 5pm.
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West Ham midfielder Michail Antonio was forced to withdraw from the England squad due to a hamstring injury, with Southgate yet to confirm a replacement as of Monday afternoon.
Andy Carroll, Danny Welbeck and Theo Walcott were among the most notable absentees from Southgate’s 26-man squad, while captain Wayne Rooney also misses out.
Sunderland’s 34-year-old striker Jermain Defoe was the most notable beneficiary of the attacking trio’s absence, with Southampton duo Nathan Remond and James Ward-Prowse and West Brom midfielder Jake Livermore among the surprise inclusions.
Lithuania's job has been made harder with a number of key absences, as Edwin Girdvainis (injury), George Freidgeimas (suspended) and Vytautas Andriuskevicius all miss out.
England squad (provisional): Fraser Forster, Joe Hart, Tom Heaton, Ryan Bertrand, Gary Cahill, Nathaniel Clyne, Phil Jones, Michael Keane, Luke Shaw, Chris Smalling, John Stones, Kyle Walker, Dele Alli, Ross Barkley, Eric Dier, Adam Lallana, Jesse Lingard, Jake Livermore, Alex Oxlade-Chamberlain, Nathan Redmond, Raheem Sterling, James Ward-Prowse, Jermain Defoe, Marcus Rashford, Jamie Vardy
England XI: Hart, Walker, Cahill, Stones, Bertrand, Dier, Alli, Lallana, Oxlade-Chamberlain, Sterling, Vardy
Lithuania XI: Setkus, Borovik, Vaitkunas, Klimavicius, Slivka, Kuklys, Zulpa, Novikov, Valskis, Chernykh, Matulevicius
2018 WORLD CUP QUALIFYING: GROUP F (EUROPEAN)
England have won the only two meetings between the two nations - 4-0 (home) and 3-0 (away) in the Euro 2016 qualifiers back in 2015.
BETTING ODDS (via 888 Sport)
- England to win: 1/9
- Lithuania to win: 19/1
- Draw: 17/2
Click here to place a bet.
Odds correct as of March 20 at 1pm.