The first leg of the quarter-final tie at Sporting Park will be Kansas City's second of five games in 15 days.
And a meeting with the CONCACAF Champions League's equal most successful club – five-time champions Cruz Azul – is a huge task.
A 94th-minute winner from Chad Barrett saw the Seattle Sounders claim a dramatic win over Sporting in their MLS season opener on Saturday.
Sporting's Argentine striker Claudio Bieler was left on the bench for the clash, perhaps with an eye to the Cruz Azul encounter.
Peter Vermes' side take on high-flying Liga MX leaders, who have made a blistering start to their Mexican league campaign.
Cruz Azul have scored 18 league goals in 10 matches, while their defence has kept most teams at bay.
That was until a shock 3-0 loss to Tigres UANL on Sunday and Cruz Azul's first league loss of the season should give Sporting hope.
The visitors are likely to be without midfielder Achille Emana, who is their leading goalscorer in the Champions League with four.
The Cameroonian looked close to returning before hurting his hamstring once more earlier in March.
Cruz Azul or Sporting will face the winner of the tie between Los Angeles Galaxy and Tijuana, who meet in California for their first leg on Wednesday.
Tijuana have been solid in Liga MX and their strike duo of Francisco Martinez and Dario Benedetto are sure to threaten the Galaxy.
The final MLS side remaining in the competition are the San Jose Earthquakes, who host Toluca in the first leg of their quarter-final.
In Raul Nava (six goals), Toluca have the competition's leading goalscorer to this stage.
Costa Rican outfit Alajuelense and Panama's Arabe Unido will also do battle for a place in the last four.
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