Surprise package Munster will make the daunting trip to Top 14 leaders Clermont on Saturday, while Saracens will take on big-spending Toulon at Twickenham on Sunday.
And ahead of this weekend's encounters we look at where the games will be won and lost... Remember you can watch all the action live on Sky Sports HD.
Clermont v Munster (Saturday, Sky Sports 1 HD from 4.30pm)
Clermont have been in irresistible form this season and they will look to continue this against the Irish giants.
The French side boast an impressive record this season of 25 wins from 32 games, with one draw and six defeats. None of those losses have come at home - with Clermont having not lost at Stade Marcel Michelin in 59 matches.
The Heineken Cup semi-final will be played at Stade de la Mosson in Montpellier, though, and Munster can take heart from Leinster's success over Clermont at the same stage last year - with that match played at Stade Chaban-Delmas in Bordeaux.
As you would expect from a side that currently leads the Top 14 and is in the last four of Europe's elite competition, Clermont have a squad that oozes class.
They have a battle-hardened and rugged front five, including the likes of Thomas Domingo, Jamie Cudmore and Nathan Hines, while Alexandre Lapandry and Julien Bonnaire are a menace in the back row.
Behind the scrum Morgan Parra is the lynchpin, with the No 9's accuracy with the boot making him such a threat. Across the back division, the Auvergne have a scary amount of gifted players - with Napolioni Nalaga (six tries in Europe this season), Wesley Fofana (five tries in six) and Sitiveni Sivivatu (three in six) brilliantly marshalled by Aurelien Rougerie.
While Clermont have been flying, Munster had been enduring a disappointing campaign - that was until they ripped up the form book in the quarter-final.
Few gave Munster a hope of beating Premiership champions Harlequins at the Stoop, however, inspired by Paul O'Connell, the Irishmen defied the odds.
Munster had only scraped into the last eight courtesy of the second best runners-up spot after finishing behind Saracens in the pool after losing two of their games.
On top of that their form in the RaboDirect PRO12 has been below-par - with Munster set to finish well adrift of the play-offs.
However they have a habit of coming good on the big occasions. They have won an impressive 91 of their 129 Heineken Cup games, including the title in 2005-06 and 2007-08, while Saturday's trip to Stade de la Mosson will be their 10th semi-final appearance.
They will need two of their European veterans, though, to rise to the occasion yet again if they are to reach the final. O'Connell, the talismanic lock, has 67 Heineken Cup appearances under his belt, while kicking king Ronan O'Gara has racked up 1,360 points in 109 games.
O'Gara will give Munster the positions to play in - so it will be up to O'Connell and Co to win the ball.
The Munster pack certainly has the quality, with Donnacha Ryan and Peter O'Mahony impressing off late.
In the backs Casey Laulala and James Downey combine for a powerful midfield, while the fit-again Simon Zebo provides the x-factor out wide.
Saracens v Toulon (Sky Sports 2 HD from 2.30pm)
Saracens will be hoping that their defeat against Gloucester in the Aviva Premiership was nothing more than a blip.
Sarries had been flying high, winning six league games on the bounce and brushing aside the challenge of last year's finalists Ulster in the Heineken Cup.
And they will be only too aware that they will need to recapture this form if they are to reach their first final.
The club were semi-finalists in 2008-09, losing narrowly to Northampton, while they crashed out in the last eight to Clermont 12 months ago. Sarries will head to Twickenham, though, confident they have learned their lessons from those defeats.
The Premiership leaders have built their game around a watertight defence and a strong kicking game. They have conceded just 30 tries in 28 games in the league and Europe, while Owen Farrell has given them the platform to build on.
Farrell has landed 92 points in the Heineken Cup this season - including a stunning 32 points in the away win against Racing Metro.
Despite the criticisms that they play a conservative style of percentage rugby, Saracens do also have a plan B as the wins over Edinburgh, Racing Metro and Ulster highlight.
With Chris Ashton, Dave Strettle and Alex Goode they certainly have the class out wide.
Up front the pack is exceptionally well-drilled and has strength in depth. Mako Vunipola, Matt Stevens, Rhys Gill, John Smith and Schalk Brits are among those vying for a place in the front row, while Steve Borthwick, Alistair Hargreaves and Moutitz Botha are class acts in the engine room.
You then have Kelly Brown, Ernst Joubert, Jackson Wray, Andy Saull and Jacques Burger scrapping it out for the back row places - so the loss of the in-form Will Fraser through injury shouldn't be an issue.
Toulon, though, are not short of strength-in-depth themselves. Their squad is like a 'who's who of world rugby' with owner Mourad Boudjellal having assembled an expensive collection of star players.
So far his 'fantasy rugby' side has yet to repay the investment with silverware - with a Top 14 final and two Amlin Challenge Cup final defeats in recent years.
Toulon, though, feel that this could be their year in Europe and domestically.
They will arrive at Twickenham fully refreshed - with the fact they have already secured a home semi-final in the Top 14 play-offs meaning they were able to rest most of their stars at the weekend.
A number of the squad will also feel at home in Sunday's surroundings, with Jonny Wilkinson, Andrew Sheridan and Simon Shaw regulars at Twickenham in the past - while fellow Englishmen Steffon Armitage and Nick Kennedy perhaps haven't won as many caps as they should have.
There is likely to be a clash of styles with Wilkinson's boot key to Toulon's hopes, while the forward battle is likely to be an intriguing affair.
Toulon certainly have the power in the pack, as they proved against Leicester in the last eight, while they are defensively solid. Armitage continues to make a mockery of his international exclusion, while Mathieu Bastareaud gets the backs over the gainline.