Villarreal will have to do what none of Arsenal's European opponents have managed in the last nine games and breach their rock-solid defence if are to deny the English side a place in a first ever Champions League final.
Arsenal equalled the record established by Ajax in the 1980s by keeping another European clean sheet as they ran out 1-0 winners in the first leg at Highbury thanks to a goal from Ivory Coast defender Kolo Toure just before halftime.
It is a tall order for the Spanish side who have struggled for goals this season and whose biggest win in their debut campaign in the Champions League was 2-1 against Everton in the third qualifying round.
They have won just one of their last eight Primera Liga matches and slumped to a 2-0 defeat at home to Real Sociedad on Saturday after coach Manuel Pellegrini decided to field a second string team against their struggling opponents.
The defeat means that Villarreal are now in 10th position in the table and their only hope of earning a Champions League place next season lies in winning the competition.
But Pellegrini believes his side can throw the form book out of the window and do what the illustrious forward lines of Real Madrid and Juventus failed to achieve in recent weeks.
"I fielded this team because we've got a very important game on Tuesday," he said after the Saturday's match. "I thought we could have done better, but I'm sure the game against Arsenal will be a different story.
Villarreal will be without suspended Italian midfielder Alessio Tacchinardi as well as injured centre-back pairing Gonzalo Rodriguez and Juan Manuel Pena.
But they will have first-choice keeper Sebastian Viera back after the Uruguayan was suspended for the first leg at Highbury.
The main weight of responsibility, however, will rest on the shoulders of Argentine playmaker Juan Roman Riquelme and striker Diego Forlan to see if they can engineer a way to prise open Arsenal's miserly defence.
Like Villarreal, Arsenal's only certain route back into next year's Champions League is by winning this year's competition after they were held to a 1-1 draw by Tottenham Hotspur on Saturday in the final north London derby at Highbury.
That result left Arsenal fifth in the league, four points behind Tottenham who will finish fourth - and take England's other place in the Champions League qualifiers - if they win their last two games of the season.
Wenger shuffled his squad before Saturday's match, leaving Thierry Henry, Francesc Fabregas and Emmanuel Eboue on the bench, while resting Freddie Ljungberg and Alexander Hleb.
All five will be expected to start against Villarreal, while Jose Antonio Reyes will be available again after serving a one-match suspension.
Swiss defender Phillipe Senderos is doubtful after injuring his knee against Spurs and his absence could leave the door open for a return for Sol Campbell who missed Saturday's game against his former team because of a broken nose.
Arsenal were far from their fluent best against their north London rivals and trailed to a 66th-minute goal from Robbie Keane.
But Henry came off the bench to salvage a draw for the home side with a beautifully executed equaliser seven minutes from time.
"We were struggling physically in the first half," said Wenger. "But that's what happens when you are playing every three days.
"I was pleased with the way we showed character and came back well and I congratulate the team. Now we must prepare for the big game on Tuesday."
Villarreal: 13-Sebastian Viera; 17-Javi Venta, 4-Cesar Arzo, 16-Quique Alvarez, 3-Rodolfo Arruabarrena; 12-Juan Pablo Sorin, 19-Marcos Senna, 6-Josico, 8-Juan Roman Riquelme, 23-Jose Mari, 5-Diego Forlan
Arsenal: 1-Jens Lehmann; 27-Emmanuel Eboue, 28-Kolo Toure, 23-Sol Campbell, 16-Mathieu Flamini; 13-Alexander Hleb, 19-Gilberto, 15-Francesc Fabregas, 7-Robert Pires or 9-Jose Antonio Reyes, 8-Frederik Ljungberg; 14-Thierry Henry
Referee: Valentin Ivanov (Russia)