Quins will bid for their 15th successive victory in all competitions this season, having won 10 Aviva Premiership games, two European ties and two LV= Cup fixtures.
But Toulouse arrive at the Twickenham Stoop with an impeccable European pedigree after being crowned Heineken Cup winners four times and currently leading France's domestic Top 14 championship.
"They set the benchmark for European rugby," Quins rugby director O'Shea said.
"It is why we want to be in the Heineken Cup to play against teams like Toulouse.
"We always talk about testing ourselves to see where we stand, and we are playing against the best side in Europe."
England number eight Nick Easter returns for Quins after he missed last weekend's Premiership victory over Wasps due to injury, with lock George Robson also back, while Benjamin Urdapilleta replaces centre Tom Casson, who suffered an ankle injury during training this week.
Quins' England wing Ugo Monye, who agreed fresh contract terms with the club earlier this week, believes the Amlin Challenge Cup holders are in fine shape as they prepare for their biggest game of a so-far memorable campaign.
"It has been fantastic to have been a witness to all the changes that have taken place at the club over the last 10 years," Monye said.
"The Quins academy has produced a number of the current first team squad and, I am sure, many more England internationals in the future.
"Being at Harlequins is not all about the playing - it becomes a part of your life.
"We are a tight-knit bunch of lads who all love playing for each other. With so many English-qualified players within the squad, we all have a common goal - playing for Quins and our country."
Toulouse, conquerors of Quins in all three previous Heineken Cup meetings, parade recent signings Luke McAlister and Luke Burgess as their half-backs, while French World Cup stars Thierry Dusautoir, Maxime Medard and Vincent Clerc also start.
Elsewhere tomorrow, unbeaten Pool Two contenders Cardiff Blues and Edinburgh meet in Wales, while Ulster entertain Pool Four opponents Aironi at Ravenhill.
"We are perhaps playing the in-form team of the group in Edinburgh - they seem to be scoring tries for fun," Blues forwards coach Justin Burnell said.
"Edinburgh play a very open and expansive game, and I think you can see from the tries they score that a lot of them are from broken play or turnovers.
"So we have to be very aware of not giving easy turnovers or kicking that ball into the wrong areas to (Tim) Visser and their back three."
The Blues are bolstered by seven players - Leigh Halfpenny, Alex Cuthbert, Jamie Roberts, Lloyd Williams, Gethin Jenkins, Bradley Davies and Sam Warburton - returning from Wales duty against Australia last weekend.
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