The hosts sit down in fourth place in Group F, already six points behind leaders England at the halfway stage and with their hopes of reaching Russia 2018 hanging by a thread.
There are many of a Scottish persuasion who believe that manager Gordon Strachan is fortunate to still be in the job, and Saturday's match could well be make or break for him.
Reports have suggested that the Scottish FA is lining up former Everton, Manchester United and Sunderland boss David Moyes as a possible replacement should Strachan lose against the Auld Enemy, but no matter who is on their wishlist, defeat is likely to see the end of Strachan's tenure.
A 1-0 victory over Slovenia in Scotland's last outing in March bought Strachan a bit more time, but their World Cup qualification hopes still look bleak and a loss to England would leave them 10 points adrift of the only automatic route to Russia with only four games remaining.
A place in the playoffs is still very much within reach, with two points separating Scotland from the runners-up spot as things stand, but second-placed Slovakia and third-placed Slovenia face the group's bottom two teams on Saturday and will be expected to pick up three points.
A draw may not even be enough for Scotland, then, but in the longer term they will at least hope to still be in the argument heading into the final set of Group F matches, which see them face their two main rivals for second place.
Whether Strachan will still be in the job at that point remains to be seen but, as damaging as defeat on Saturday could be, there is nothing like a win over the English to get the Scotland support back behind you.
Scotland are unbeaten in their last five matches on home soil and world champions Germany are the only visiting team to have beaten them at home since November 2014, which was incidentally when England last visited Hampden Park.
The Tartan Army have not exactly been inspiring in front of their own fans during the current qualification campaign, though, drawing with Lithuania before scraping a win over Slovenia in their last outing.
Strachan knows that an improvement is needed if they are to claim a famous victory over England and perhaps keep him in the job, but Scotland will undoubtedly be up for the fight in what could be their last-chance saloon as far as World Cup qualification is concerned.
Recent form: WDLLW
Recent form (all competitions): WDLLDW
It has certainly not been a smooth-sailing qualification campaign for England so far, with managerial upheaval and the latest boss Gareth Southgate having only had one qualifier in permanent charge of the team at the halfway stage.
However, the results have not taken a hit in that time and England remain firmly in the driving seat for the automatic route into next summer's World Cup, with four points separating them from Slovakia in second.
What's more, the Three Lions appear to have got their trickiest matches out of the way having already travelled to Slovakia and Slovenia. The only away matches after Saturday will be in Malta and Lithuania which, considering England's imperious record at Wembley, should allow a relatively routine passage to Russia.
England have played seven times since their infamous Euro 2016 exit at the hands of Iceland, and the only team to beat them in that time has been world champions Germany - a narrow 1-0 victory courtesy of a Lukas Podolski screamer on his international farewell.
Southgate's side were actually on top for the majority of that match, but they failed to make their chances pay and were duly punished - a reminder of the difference in quality between qualifying for the World Cup and the tournament itself.
As is often the case, the qualifying aspect is going well for England so far - they have dropped just two points and are the only team yet to concede a goal in the group stages.
However, they have also only scored eight times, which is the lowest tally of any team currently en route to the finals. England have scored only one goal in their last three away games - a run which stretches back to their thrilling 3-2 triumph over Germany in Berlin last March.
Just one of England's last four away qualifiers have ended in victory, but they have not been beaten on their travels in qualification since a 1-0 defeat at the hands of Ukraine in October 2009.
Southgate and co will be on the road again on Tuesday when they face France in a glamour friendly in Paris, but while that fixture may be more eye-catching, it is Saturday's battle between the oldest enemies which carries the most importance.
Recent form: WWDWW
Recent form (all competitions): WDWDLW
Harry Kane is expected to lead the line for England as he looks to score his first international goal since May 2016.
Perhaps the biggest selection dilemma for Southgate involves two of Kane's club teammates, though, with Kyle Walker and the uncapped Kieran Trippier now battling for the right-back spot at international level in addition to club.
Kieran Tierney has been passed fit for the match and will play wearing a special gumshield after picking up a facial injury in Celtic's Scottish Cup final win over Aberdeen.
Scotland possible starting lineup:
Gordon; Tierney, Martin, Mulgrew, Robertson; McArthur, Brown; Forrest, Armstrong, Snodgrass; Griffiths
England possible starting lineup:
Hart; Walker, Cahill, Stones, Bertrand; Lallana, Dier, Dele; Lingard, Kane, Sterling
Head To Head
England have dominated this fixture in recent times, winning all three meetings since the turn of the century and scoring three times in each of those.
Indeed, the Three Lions have won seven of their last eight clashes with the Auld Enemy and have only lost one of their last 10 - a run which stretches back to 1985.
We say: Scotland 0-1 England
Expect a fever pitch atmosphere at Hampden Park, but the action on the field may not live up to the excitement in the stands. England have been low-scoring away from home recently but should have enough in their locker to scrape an all-important victory against their oldest rivals.