Sale, despite qualifying as England's top seeds, are in the same pool as French giants Stade Francais and star-studded Welsh challengers Ospreys.
Saint-Andre's men launch their European campaign against the Ospreys at Swansea's Liberty Stadium on Friday night - a ground where Stade Francais lost last season and Leicester only won through an injury-time try.
With Italians Calvisano making up the Pool Three numbers, Sale know victory tonight or in Paris just before Christmas would enhance their quarter-final claims.
"Every match will be vital, and to have any hope of progression we must take maximum points from our three home games and look to win at least two on the road," said Sharks rugby director Saint-Andre.
"We are in an incredibly tough pool, and the fact we must play the top team from France, Wales and Italy despite being the number one seed from England, shows just how hard our group is.
"We must target winning the group, as I cannot see a second-place finish getting through to the quarter-final."
Sale progressed as one of two best runners-up last term, but a lowly seventh seeding meant they faced Biarritz away in the quarter-finals and subsequently bowed out.
The Ospreys, whose three previous Heineken Cup campaigns all ended in pool stage exits, parade a full armoury of talent, including Gavin Henson, Justin Marshall, Shane Williams and Ryan Jones.
"This group contains three of the biggest packs in European rugby, and it will take a super-human effort from us if we are to progress," said Ospreys head coach Lyn Jones.
"I watched Sale demolish London Irish last weekend, and I was really impressed with the way they are playing.
"They didn't just beat Irish, they man-handled them into submission. We will have to match their physicality up front if we are to get anything out of this game."
London Irish rugby director Brian Smith, meanwhile, has likened Friday night's Pool Five opponents Llanelli Scarlets to a southern hemisphere Super 14 side.
Irish, Premiership play-off title contenders last term, have struggled to recapture that form this season, so Llanelli will not fear their Madejski Stadium mission.
"The Scarlets are a very gifted side and play a Super 14 style of game," said Smith, who welcomes back captain Mike Catt after injury, although fly-half Riki Flutey and lock Kieran Roche both face late fitness tests.
"We are expecting them to throw the ball around, so it should be a great contest. The short turnaround from last Sunday's game against Sale has made our task more difficult, but we are quietly confident."
Elsewhere on the opening night of Heineken Cup action, Edinburgh travel to Stade Armandie where Agen await them in Pool Two, while Borders make a top-flight European return by hosting tournament debutants and Pool Six outsiders Overmach Parma.
loucester's Pool Two appointment with Leinster in Dublin is the highlight of a Saturday programme that features only one English club, with Cardiff Blues visiting Pool Four rivals Bourgoin, Pool Six favourites Toulouse travelling to Ulster, Treviso entertaining Perpignan in Pool One and a Pool Three clash scheduled between Calvisano and Stade Francais.
Cardiff have failed to record a Heineken Cup win on French soil in 11 previous attempts, but head coach David Young is relishing a group that also includes reigning European champions Munster and twice-tournament winners Leicester.
"We have shown with our performances (this season) that we are really going out to win games, not just hoping that we can win them," said Young.
"We are a much better all-round squad and team at the moment, and we have learned from some of the things we were not doing well and are getting better for that.
"Someone has to win the group, and I don't see why it cannot be us."