The Cardinal have had the Trojans' number in recent years. Stanford won the last three matchups, and four of the last five.
In 2011, the two teams battled in an epic contest at the Coliseum in Los Angeles, with the Cardinal edging the Trojans in triple overtime, 56-48. It was perhaps the most exciting game for either school, and it showcased two high-profile quarterbacks.
"I think you can say in the last five years they've been three of the most exciting games you can imagine starting with the big upset win down there," said Stanford head coach David Shaw. "We're different teams but we play some exciting football the last two years."
But this time the Cardinal are without superstar quarterback Andrew Luck, who was selected with the top pick in the 2012 NFL Draft.
The roles have reversed, with USC having the edge at quarterback. Matt Barkley is expected to be the first quarterback selected in the 2013 NFL Draft, and is a frontrunner for the Heisman Trophy.
Barkley is coming off a six-touchdown effort against the Syracuse Orange, in a game that was played under lightning conditions in New Jersey. The star passer didn't throw for 200 yards in the game, and also had an interception, so Barkley will probably be looking to rebound from the effort.
Barkley has a pair of star wide outs in Marqise Lee and Robert Woods, as the duo make up perhaps the best receiving tandem in the nation. The Trojan offense also boast a pair of elite running backs in Silas Redd and Curtis McNeal.
The Stanford defense will be tested against this high-octane Trojan offense. The Cardinal conceded 288 yards to San Jose State, and 385 yards against Duke. Neither San Jose State nor Duke are expected to be ranked in the Top 25 this season.
Meanwhile, the Stanford offense only accrued 280 total yards against San Jose State, and 373 against Duke. While the USC defense have received some criticism this season, many of the starters have enough experience to hold off an offense that often seemed sluggish in their first two games.
Stanford will rely on Josh Nunes to step up. The junior quarterback has only thrown for 400 yards in his first two games as starter, but only has one interception. Replacing Luck is obviously a difficult challenge, but the Nunes has shown patience running the Stanford offense.
Running back Stephan Taylor is also a key player to watch. The senior tail back is coming off two-straight seasons of over 1,000 rushing yards.
The Trojans have multiple reasons to be excited about this matchup. Lane Kiffin's squad want to bounce back from a supbar effort against Syracuse, to convincingly defeat the Cardinal, and to show the nation that they are a legitimate contender for the National Championship.
The Cardinal are ranked No. 21 for a reason, as the squad is filled with talented upperclassmen like linebacker Chase Thomas, and tight end Levine Toilolo. Stanford would like nothing more than to climb the rankings by defeating a top team, and earn a chance to go to the Pac-12 title game.
The game starts at 4:30 pacific time, and will be televised by FOX Sports.
BETTING ODDS: USC favored by 9 points
PREDICTION: Barkley will be eager to have a big game, and should find his receivers with ease. Expect another big game from Redd, as well. Stanford can make this interesting because of their disciplined approach, but it won't be enough to hold off USC.
PREDICTED SCORE: USC over Stanford, 38-20