Although titleholders Barcelona are unlikely to repeat the 7-1 aggregate win they pulled off in the first meeting of the two sides in the 1959-60 European Cup, they have looked unstoppable in the Champions League this season.
Seven-times champions Milan, on the other hand, have been struggling with injuries in the run-up to the quarterfinal first-leg tie, a repeat of the 1994 final which the Italians won 4-0.
Pep Guardiola's side have won seven and drawn one of their eight games, scoring 30 goals at an average of nearly four per match, and beat Milan 3-2 at the San Siro in the group stage.
They have not lost in their last 14 Champions League games and are unbeaten in their last five against the Italians.
Messi has scored 18 goals in his last eight Barcelona matches and a hat trick for Argentina. His club tally included the first five-goal haul in the Champions League, against Bayer Leverkusen.
He needs one more goal to break the Champions League season record of 12 goals, set by himself last season and Ruud van Nistelrooy in 2003, and also notch up his 50th goal of the competition.
Last week, Messi broke the Barcelona scoring record with his 234th goal for the club and his tally of 55 goals this season in all competitions is already a Spanish record with two months still to play.
The outlook became bleaker for Milan after Thiago Silva, the linchpin of their defence, joined Milan's lengthy injured list, the Brazilian limping off early during the 2-1 win over AS Roma on Saturday.
Right back Ignazio Abate and Brazilian forwards Robinho and Alexandre Pato are also sidelined while the Serie A leaders and defending champions will miss the intimidating presence of Mark Van Bommel in midfield as the Dutchman is suspended.
They good news is that Kevin-Prince Boateng, who scored one of the goals of the competition in Barcelona's 3-2 win in November, is fit again while Zlatan Ibrahimovic has been in outstanding form in attack.
The volatile Swede, who left Barcelona in acrimonious circumstances 18 months ago, remains Milan's trump card with 22 goals in Serie A this season and five in the Champions League.
Although Milan have a four-point lead at the top of Serie A, they have struggled in big matches this season, and were outplayed in both group-stage meetings against Barcelona, including the 2-2 draw at Nou Camp.
They have yet to beat Juventus in four attempts, lost 1-0 to archrivals Inter in the Milan derby in January and reached the quarterfinals by the skin of their teeth after a 3-0 defeat to Arsenal in the second leg of their round-of-16 tie.
Milan were criticised for fielding Thiago Silva against Roma but chief executive Adriano Galliani defended their policy yesterday.
"We knew that Thiago Silva had a problem, but he seemed fine," Galliani told reporters. "Then he got injured and everyone is talking about it.
"Nobody knew that Zlatan Ibrahimovic played with a bad back," added Galliani. "If he had not played then maybe we may not have won. Risks are part of the game.
"As for Barcelona, we will be meeting the holders who are playing the best football in the world.
"We have not been at all fortunate in the draw but then neither have Barcelona. Milan have been used to facing these types of matches for many years and I am pleased when Milan battle.
"Last year we were in the battle for the title with Inter and this year it is Juventus. The opponents change but we are always there. Win, lose or draw it is important to stay the top club."
Guardiola, whose side trail Real Madrid by six points in La Liga, dismissed Milan's injury problems.
"If we are expecting Milan to play below their usual standard, then we're wrong," he said after the draw was made. "The fact that we did well in the group stage doesn't mean we are going to win this tie."
AC Milan: 32-Christian Abbiati; 25-Daniele Bonera; 5-Philippe Mexes, 33-Alessandro Nesta, 77-Luca Antonini; 22-Antonio Nocerino, 23-Massimo Ambrosini, 27-Kevin-Prince Boateng, 28-Urby Emanuelson; 11-Zlatan Ibrahimovic, 21-Maxi Lopez
Barcelona: 1-Victor Valdes; 2-Dani Alves, 14-Javier Mascherano, 3-Gerard Pique, 5-Carles Puyol; 6- Xavi, 8-Andres Iniesta, 16-Sergio Busquets, 4-Cesc Fabregas, 10-Lionel Messi, 9-Alexis Sanchez. (Writing by Brian Homewood in Berne; Editing by Clare Fallon)