Having opened their qualification campaign with three defeats, Gary Speed's side know they have a mountain to climb if they are to end their long wait for a place at a major tournament.
The Dragons are fast running out of time in their efforts to reach the 2012 European Championships in Ukraine and Poland, suggesting they are poised for further international heartache.
Confidence needs to be restored to a side that has tasted defeat on its last four outings, scoring only one goal in the process.
Speed will be hoping that Wales can turn the corner on Saturday, in his first competitive fixture since inheriting the national reins from John Toshack.
It could be that a meeting with England is just what the Dragons need, with a full house in Cardiff expected to generate a red-hot atmosphere.
The Three Lions will enter the game, though, knowing that they have prevailed in the last two meetings between the two nations - during qualification for the 2006 World Cup.
They have, however, alternated between victory and defeat on their last five visits to Wales and were that record to continue this weekend, they would leave with nothing.
England's recent away record suggests they are capable of bucking that trend, with a defeat in the Ukraine after they had already booked their place at the 2010 World Cup representing the only setback they have suffered on the road in their last six outings.
Goals have also been in plentiful supply for Fabio Capello's men of late, with only Montenegro and Algeria having kept them out in their last 13 fixtures.
More goals and another three points against Wales this weekend would be enough to take England to the top of Group G on goal difference, with current leaders Montenegro not in action.
Wales' build-up to the game has been dominated by contrasting fortunes for two of their most promising young stars.
News that Tottenham winger Gareth Bale has suffered a hamstring injury and will play no part on Saturday has come as a major blow to the hosts, as he was widely acknowledged as the man most capable of causing England problems.
Speed is, however, delighted to have Arsenal midfielder Aaron Ramsey available again and has opted to hand the 20-year-old the captain's armband, making him Wales' youngest-ever skipper.
That role was up for grabs after Craig Bellamy decided to step aside, but the on-loan Cardiff striker will still be an important part of Speed's plans.
Sam Vokes, who has recently agreed a loan switch to Norwich, has replaced the injured Robert Earnshaw in the Wales squad and will be vying for a striking berth alongside the likes of Steve Morison, Simon Church and Ched Evans.
England's preparations have also generated plenty of headlines, with Capello having decided to hand John Terry the captaincy again, 13 months after the Chelsea centre-half was stripped of the honour and replaced by Rio Ferdinand.
Injuries to Manchester United defender Ferdinand and vice-captain Steven Gerrard, who will again be missing this weekend, convinced the Italian that it was time for a U-turn.
The Three Lions saw Birmingham goalkeeper Ben Foster withdraw from the squad on Friday with a throat infection and his place has gone to West Brom's Scott Carson.
Everton's Phil Jagielka is expected to provide cover for Ferdinand, while Jack Wilshere is a confirmed starter in midfield.
Andy Carroll will battle with Jermain Defoe, Darren Bent and Peter Crouch for the right to partner Wayne Rooney.
Kyle Walker, currently taking in a loan spell at Aston Villa, and Wolves winger Matt Jarvis will be hoping to make their senior debuts in Cardiff.