The Manchester City manager must decide how many of City's best players to risk for at the Riverside Stadium.
Guardiola must decide how many of City's best players to risk for at the Riverside Stadium as they have a crucial Champions League last 16 second leg clash with Monaco four days later.
The FA Cup offers the more realistic prospect of Guardiola's first trophy with City, but the Spaniard's success in Europe was a key factor in the decision to bring him to Manchester last year.
The former Barcelona and Bayern Munich boss will find his skills tested to the limit in what is a defining week for City's season.
His most recent attempt at squad rotation failed when Guardiola decided to start Wednesday's Premier League home game against Stoke without his two best creative players.
David Silva was named as a substitute and Raheem Sterling was rested altogether as City drew 0-0, leaving them 10 points behind leaders Chelsea.
Guardiola has rested players for each of City's FA Cup games so far, but there are signs that he is taking the competition more seriously the further he progresses.
Having made eight changes for their goalless fifth round tie at Huddersfield last month, he made only four for the replay, which City won 5-1.
Claudio Bravo, now the second-choice goalkeeper for league games, has come back in for the last two FA Cup ties and should play again at the Riverside Stadium, while full-back Pablo Zabaleta has also tended to be used in the competition.
Perhaps the biggest question revolves around Sergio Aguero.
The Argentina striker was demoted to the bench following the January arrival of Gabriel Jesus from Brazilian club Palmeiras.
Yet since Jesus broke his foot against Bournemouth on February 13, Aguero has proved indispensable.
He scored twice in 5-3 first leg win against Monaco, and is City's best hope of the away goal they may well need in the principality to secure European progress.
Guardiola cannot afford an injury to the striker, and so may decide to field Kelechi Iheanacho against Middlesbrough instead.
City midfielder Yaya Toure hinted that there will be some changes on Saturday, saying: "We've got two games now where we need all the players.
"We have to try to do the business. Middlesbrough is going to be a tough, tough game.
"They've had a rest for a week. We'll try to do our best. Of course, one trophy would be very welcome for us."
Meanwhile, Middlesbrough boss Aitor Karanka insists he has the full backing of chairman Steve Gibson despite seeing his side drop into the relegation zone for the first time this season after a 10-game winless Premier League run.
Middlesbrough's progress to the last eight of the Cup has helped to relieve the pressure on Karanka, who came under fire from sections of the club's travelling support during the 2-0 defeat at Stoke, which stretched the Teessiders' wait for a league victory beyond three months.
Karanka has held talks this week with Gibson and the Spaniard conceded: "The last two weeks have been really bad."
Asked if he still has Gibson's backing, he added: "Of course. I've spoken to the chairman since the weekend.
"We discussed the amazing opportunity we have to make it to Wembley by winning on Saturday. We know we have to be positive and believe in what we're doing.
"The most difficult moment for me at this club was when I arrived three years ago and we lost three of the first four games.
"Back then he told me he had confidence in me and that was a big thing. He doesn't have to tell me every day that he has confidence in me.
"I don't really care what the critics say, because I'm my own biggest critic."