The Premiership's new boys were given a harsh introduction to life in Europe by Stade Français in Round 1, when they ended up on the end of a 68-19 hammering at the Kassam Stadium, but bounced back to beat I Cavalieri Prato 32-31 thanks to Alex Davies' late penalty.
Head coach Lyn Jones makes 14 changes from the side that defeated London Irish 15-9 last Saturday, with full-back Tom Arscott the only player to retain his starting place.
"We're still in the competition and this is a great opportunity for several players to stake their claim for Aviva Premiership selection," said Jones.
"This group of players is extremely motivated and has really prepared well this week, so we're looking forward to a good performance.
"Every game is important to us and we want to win every single match. We understand where we are now and we mustn't lose focus of where we want to be at the end of the season.
"All games are big games and we've got to take each one as they come."
Jones is expecting a tough physical battle at the Stade Lesdiguiéres, and Welsh will need to be up for the challenge as they look to build on the momentum of their Premiership victory over London Irish.
"England showed how to play against good sides and that's to close their space down. We'll be challenging our boys to get off the line and knock them down," he said.
London Welsh back-row forward Daniel Browne has enjoyed two spells with Grenoble, and last season helped the club gain promotion to the Top 14.
"Grenoble are a bit like London Welsh, they got promoted and have dramatically changed their squad. Daniel was keen to play this weekend but it was his turn to miss out," added Jones.
Grenoble: 15 Joaquim Tuculet, 14 Viliame Waqaseduadua, 13 Rida Jaouher, 12 Aloisio Butonidualevu, 11 Florian Ninard, 10 James Hart, 9 Clement Darbo, 8 Flavein Nouhaillaguet, 7 Jonathan Best, 6 Fabien Alexandre, 5 Andrew Farley, 4 Thibault Rey, 3 tbc, 2 Vincent Campo, 1 Romain David.
Replacements: 16 Gregory Fabro, 17 Anthony Hegarty, 18 Henri Vanderglas, 19 Alexandre Pollard, 20 Valentin Courrent, 21 Fabien Gengenbacher, 22 Blair Stewart, 23 Karim Kouider.
London Welsh: 15 Tom Arscott, 14 Phillip Mackenzie, 13 James Lewis, 12 Seb Jewell, 11 Ashley Smith, 10 Alex Davies, 9 Nick Runciman, 8 Alfie Vaeluaga Toala, 7 Mike Hills, 6 Lee Beach, 5 Matt Corker, 4 Adam Brown, 3 Arthur Joly, 2 Greg Bateman, 1 Tom Bristow.
Replacements: 16 Willie Hafu, 17 Billy Moss, 18 James Tideswell, 19 Mike Denbee, 20 Jon Mills, 21 Matt Keyte, 22 Simon Whatling, 23 Nick Scott.
Kick-off 6.30pm GMT
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