The Owls, winless in their past four Championship matches, desperately require three points to reignite their faltering promotion bid.
There are no easy assignments in the mad, unpredictable world of the second tier but the Hatters are deep in relegation trouble.
Graeme Jones's side have the worst home record in the division, having taken a meagre 18 points from 15 matches in their own backyard.
And Luton have lost six of their last seven outings in the league, firing blanks in losses West Bromwich Albion and Cardiff City. They were denied a precious draw last time out after a late strike by in-form Bluebirds dangerman Lee Tomlin.
Jones, appointed Hatters boss in May 2019, said: "We set up with the diamond and we out-possessed them, we created more chances than them, we had more shots on target than them, the boys gave absolutely everything they’ve got.
“The game boils down to two moments, where Tomlin, he doesn't hope to score, he makes sure he can score.
"We had a really good opportunity with Tunni (Ryan Tunnicliffe), an incredible one-on-one with Harry, and Collo’s header.
“You have to take them if you're going to win the game and we didn't, that was the difference.
“We lost the game, with the opportunities we have that we didn’t take and the one opportunity they had was in the back of the net.”