Wales and England have met 103 times since 1879 but Tuesday's game is the first time they have played each other at a World Cup finals.
Qualification for the last 16 is at stake for both teams at Ahmad Bin Ali Stadium, although England are in by far the stronger position after two matches in Group B.
You can watch the game live on BBC One and the BBC Sport website, with coverage starting at 18:00 GMT and kick-off an hour later.
Can Wales pull off a shock result that could rescue a disappointing tournament, or will England be back to their best after their below-par display against the United States and march into the knockout rounds as group winners?
Former Wales defender Danny Gabbidon and ex-Three Lions midfielder Jermaine Jenas are sharing co-commentary duties on the game, and here they talk about where it will be won and lost.
Danny Gabbidon: Wales defender Ben Davies has talked about how they could use the United States' approach as a blueprint for how to cause England problems but it is very difficult to play that way.
The US are quite a unique team with a high-energy style and, all through the team and on their bench, there are athletes - they are a very fit side.
So their way of playing suits them, and they have been doing it for some time too.
Wales don't usually play like that so it is a big ask for them to suddenly start now, but there are still elements they can take away from the US performance and look to replicate, like their positivity.
There was no fear there - they didn't care they were playing England. It was a case of 'this is how WE play'.
That kind of identity is what Wales need to find again, not just for this game but for after their World Cup is over.
So we might see a different game plan here from Rob Page, where it might be more of a containment job to begin with. We have got to be defensively solid and organised, and then look to hit England on the break.
England have struggled down the years to break down teams that sit with a low block and make it difficult for them. Wales can do that but they also have to hurt them. The ball will probably go up to Kieffer Moore, and from there out to the wide players and our runners.
Jermaine Jenas: Both teams go into this game wanting to find a performance for different reasons: Wales probably to sign off with one, and England to take one forward into the knockout stages.
This feels like the end of an era for this Wales team but if Gareth Bale, Aaron Ramsey and Joe Allen - who are all in their 30s and unlikely to play in another World Cup - want a big send-off, then this provides it.
It doesn't get much bigger than playing England at a World Cup and that makes them dangerous opposition, regardless of the fact they are extremely unlikely to get out of the group.
It's not just those three - the whole team will be desperate to do better here after couple of disappointing displays in Qatar.
For them to find the performance they want will be fully down to emotion, their fans and knowing what it means to the story of their career, rather than being able to tactically put something together to beat England, because on that level they are nowhere near as good.
Danny Gabbidon: For whatever reason, Wales have not had the right balance in midfield at this World Cup and we have left ourselves very open on the counter-attack.
That needs to be sorted out, otherwise England are going to have a very easy day.
But I don't think Wales will just try to do a defensive job on them. They will try to do more than that, because they know what the occasion means.
The Wales fans in Qatar don't care about the result or qualifying for the last 16. I have spoken to some of them out here and they have already forgotten about the past two performances.
They just want the team to go out and give it their all, and play to the level they know they can.
So let's forget what it means about getting out of the group. We could lose but still have a really positive day if we approach the game in the right way.
This time, let's get the gameplan right, then go and execute it properly, but we should remember we have got nothing to lose any more.
Jermaine Jenas: England were really tentative against the United States and it was a massive shock to the system after everyone felt like we had just come out of a dark tunnel with our attacking outlook against Iran.
The Iran game had made me think 'yes, this is finally what we've been waiting to see' but tactically, they were completely out-thought by the US, and looked really tired too.
Everything felt very samey, which is a worry.
We have had some big success reaching the semi-final and final of the past two major tournaments, which is amazing, but I think we have to admit we have not done it in a really clinical manner. A lot of the time, we have just been reasonably efficient and not very easy on the eye.
When you know your group of players well, like Southgate does, you trust them and you might be thinking: Just go and let them do what they need to do.
But I don't think we were set up in the right way against the US with our tactics or our personnel, and then we did nothing to change it during the game.
Southgate has got to start making changes quicker and have a bigger influence on these players when they are on the pitch - and he has to mix up his squad now, even if he doesn't want to.
I would make wholesale changes for this game, based on the fact we have so much depth that we should be able to win this game anyway.
That probably won't happen, though. I think if even if Southgate makes only two changes, then that is massive for him - but not making more will have a knock-on effect going into the latter stages of the tournament.