Sporting Kansas City face a huge test against Portland in MLS on Saturday, while the Los Angeles Galaxy visit Real Salt Lake.
Kansas City sit top of the Eastern Conference despite largely thanks to Claudio Bieler's four goals this season.
Sporting were beaten 2-0 by the LA Galaxy on Saturday and the Timbers will be another tough encounter at Livestrong Sporting Park.
Portland are unbeaten in five matches and only a late goal from Adam Jahn denied them a third straight win as they drew 1-1 with the San Jose Earthquakes.
Stopping Bieler would go a long way toward securing a win, with the Argentine having scored half of Sporting's goals this season.
For the Timbers, Will and Ryan Johnson have scored three goals each.
In an important clash in the Western Conference, second-placed Real Salt Lake will be looking to move above the LA Galaxy.
The Galaxy broke a four-game winless run with the victory over Kansas City and coach Bruce Arena will be hoping it kick-starts their season.
The New York Red Bulls will go into their meeting with Toronto FC as favourites as they look for consecutive wins for the first time this campaign.
Chicago have recovered from their poor start but will need to cause an upset if they are to overcome the Montreal Impact.
Western Conference leaders Dallas, who are eight points clear at the top, should be too good for the struggling Vancouver Whitecaps.
In the only game on Sunday, the Houston Dynamo welcome the Colorado Rapids to BBVA Compass Stadium.
The Philadelphia Union travel to Gillette Stadium to meet the New England Revolution and MLS top-scorer Jack McInerney will be looking to add to his tally of six goals.
DC United can move off the bottom of the Eastern Conference with a win at Columbus Crew.
Mid-table Western Conference sides Chivas USA and the San Jose Earthquakes do battle on Saturday.