With 11 Lombardi Trophies and 13 Super Bowl appearances between the two squads, both franchises are looking to add to their total in the upcoming NFL playoffs.
For San Francisco, an unpredictable trip to the Super Bowl in coach Jim Harbaugh's inaugural season would be greatly aided by a bye week in the NFC playoffs. As it stands, the 49ers and New Orleans Saints share a 10-3 record.
While the 49ers are assured a home playoff game by winning the NFC West, the Steelers face a more stark reality: Any slip-up will likely cost them a shot to win the AFC North.
In a race with their rivals, the Baltimore Ravens travel to San Diego and Cincinnati in the coming weeks. This gives Pittsburgh some hope for truly being the "Steal City," taking the AFC North Championship from Baltimore despite having been swept in the season series.
With stakes so high, the stage is set for a very marketable Monday Night Football game.
How will Ben Roethlisberger fare on his injured ankle?
Can the Steelers play a clean road game and, after traveling across the continental United States, avoid the woes that tend to coincide with long-distance trips?
Will the 49ers stave off New Orleans in an effort to ensure their being one home win from the NFC Championship Game?
With so many questions to be answered, tension should be rife for this inter-conference battle. These are 10 things Steelers fans should watch for during the road trip to California.