Inverness knocked out Premiership side Livingston in the fifth round while Kilmarnock made it to the final eight by dumping Dundee United out of cup competition for the second time this season.
Match preview
Half an hour into their first Scottish Cup tie of the season, Inverness were still trailing fourth-tier Stirling Albion before recovering to prevail 3-2 back in November.
Inverness were then beaten in the fourth round by fellow Championship outfit Queen's Park but earned a reprieve when it emerged that their opponents had fielded an ineligible player, setting up a tie against European-chasing Livingston.
Second-half goals from Billy Mckay and captain Sean Welsh against the top-tier side last month secured a famous victory for the 2015 cup winners.
Caley Thistle warmed up for the all-important cup tie by beating Kilmarnock's county rivals Ayr United 2-1 away from home last weekend in the club's first victory since defeating Livingston - Inverness lie sixth in the Championship, seven points behind a playoff spot with nine games left.
Billy Dodds steered Inverness into the Championship playoffs in his debut season in the dugout last term but watched on as his side were painfully dismantled 4-0 in the second leg of the final against St Johnstone.
Kilmarnock avoided any playoff heartbreak by finishing top of last season's Championship - eight points ahead of Inverness - but only struck upon promotion form once Derek McInnes was appointed in January.
The 51-year-old former Aberdeen boss inherited a Killie side which was fourth in the table but steered them to 34 points from his 17 league games at the helm, overtaking Inverness and Arbroath to ensure Kilmarnock bounced straight back to the top flight.
Killie are in danger of lasting just as long in the Premiership as they are slumped in 11th place, narrowly above rock-bottom Dundee United in the relegation playoff spot.
Kilmarnock's struggles have clearly stemmed from a woeful away record with McInnes's side yet to win a single league game on the road - although, Killie did defeat Dundee United in Tannadice in the previous round of the Scottish Cup.
Inverness beat Killie 2-1 when McInnes's side travelled to Caledonian Stadium in the Championship last April and have not lost to the Ayrshire outfit since England international Terry Butcher was in charge back in 2010.
Inverness Caledonian Thistle Scottish Cup form:
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Kilmarnock Scottish Cup form:
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Team News
Inverness have been without Shane Sutherland all season since the 32-year-old striker ruptured his cruciate ligament, an injury which will certainly sideline him this weekend but perhaps for the remainder of his time at the club as his contract winds down this summer.
Tom Walsh managed to muster 67 minutes for Caley Thistle this term before suffering the same season-ending injury while Roddy MacGregor has been out since October with an ankle problem.
Doubts linger over Kilmarnock's Liam Donnelly as the midfielder looks set to miss yet another match during an injury-riddled campaign.
Ben Chrisene is not expected back from a knee issue as soon as Friday evening while Innes Cameron's wait for a first appearance since the World Cup is set to drag on.
Kyle Vassell scored the only goal of Kilmarnock's fifth-round victory against Dundee United and is available once again after sitting out the past two matches through suspension.
Jordan Jones added some much-needed thrust to Kilmarnock's attack when he came on at half time in last weekend's 3-1 defeat to Rangers and may have forced his way into McInnes's starting XI.
Inverness Caledonian Thistle possible starting lineup:
Ridgers; Carson, Duffy, Devine, Harper; Henderson, Allardice, Welsh, MacKay; Shaw, Mckay
Kilmarnock possible starting lineup:
Walker; Alebiosu, Wright, Dorsett, Chambers; Jones, Alston, Power, McKenzie; Doidge, Armstrong