However a word of warning to those in the upper echelons drawn against lower league opposition – there is always one upset.
That may sound like a sweeping generalisation but the fact remains that in seven of the last eight seasons a Premier League club has fallen to a foe from the Championship or below at this stage of the competition.
Last season, both Sunderland and Stoke fell to teams at least one tier below them, with the former being brushed aside by League 1 Bradford City.
While third tier Shrewsbury are 8/1 shots to depose Manchester United on Monday evening, Ladbrokes are offering a price of 9/4 that two or more lower league sides knock out top-flight opposition this weekend.
The most likely of those appears to be Reading who are actually chalked up as 13/8 favourites to defeat Tony Pulis’ West Brom.
The Royals have some decent cup pedigree in recent years with their semi final appearance last year the third time in six seasons that they have reached at least the last eight.
Brian McDermott’s side have been tough to break down at the Madejski Stadium of late, keeping three straight clean sheets in front of their own fans.
The Baggies needed penalties to overcome League One Peterborough last time out after being outplayed for much of the game at London Road and could well be one of the top tier to fall by the wayside.
At Vicarage Road it could be a case of one goal deciding it, with Watford’s cup games this term barely giving the scoreboard a work-out.
Their two FA Cup fixtures to date have ended 1-0 in their favour, while they were beaten 1-0 by Preston in the Capital One Cup third round.
Opponents Leeds have only conceded two goals in their three cup exertions this term too and might be a hint of value to provide a shock at 19/4 at a venue they have only lost at in two of their last eight visits.
Blackburn Rovers have reached this stage of the competition by seeing off League Two opposition Oxford United and Newport County and haven’t beaten Sunday’s opponents West Ham in 11 meetings, but hey, this is the FA Cup afterall.
The first opportunity for a Championship side to cause a scalp though comes at the Emirates when Hull face the Gunners for the fourth time in the competition in seven years.
The Tigers went two-nil up against Arsene Wenger’s men in the 2014 final, before an excellent fight-back handed the Londoners the cup.
They will need to hold out better this time if they are to claim the scalp of the in-form Premier League side who have won 11 of their last 14 matches in front of their own fans.
But with the Gunners potentially having one-eye on Tuesday’s tie against Barcelona in the Champions League, who knows what will happen.
The odds do suggest that one Premier League club will be sent packing by their Championship or League One counterparts over the weekend as the sides duke it out for a last eight spot in the world’s oldest cup competition.
All odds and markets correct as of the date of publishing