While both teams have not made the playoffs since the 2002 season, the two squads look to enter the 2011 season hoping things will be different this time around. The Raiders made major strides in developing their offense after finishing 8-8, while the 'Niners sputtered in the final season of coach Mike Singletary.
While the outcome of the game will have little overall importance, fans of both teams know there is a high level of pride that always comes into play when the two meet. The game will also give an edge in the preseason exhibition rivalry, which is currently tied at 19-19.
Here are six things to watch for during Saturday's action.
The 49ers' offensive line was downright awful last week, allowing the frequently blitzing New Orleans Saints six sacks, including a huge hit on quarterback Alex Smith on the first drive. Rookie quarterback Colin Kaepernick's first drive was finished on three sacks in a row.
While head coach Jim Harbaugh has stressed the importance of improving the line's play, there are some major questions that are still unanswered.
Most importantly, the center position battle has not been decided, which could shift the playing status of several players. Center/guard Adam Snyder took a majority of the first team snaps last week, but newly signed center Jonathan Goodwin should also be in the mix.
While both quarterbacks, Alex Smith and Colin Kaepernick, showed signs of struggling in Week 1 of the preseason, the two will look to rebound in a major way.
All signs point for the both of them to put up better numbers.
Josh McCown may also get some reps to show what he could offer after being signed earlier in the week.
The 'Niners hope they can continue to see production out of their rising rookie players.
Outside linebacker Aldon Smith exceeded expectations with a prolific game in the Big Easy, racking up five tackles, a sack and a forced fumble while working with the second-team defense.
Also impressing in early play was running back Kendall Hunter, who picked up 29 yards on seven carries. Chris Culliver also had a decent showing in his debut.
Look to see to some rookies stepping up tonight.
While the Raiders' secondary has been questioned after getting blown out by the Arizona Cardinals, the 49ers' backline has plenty of questions of their own. While safeties Dashon Goldson and Donte Whitner have received rave reviews from coaches, injuries have held off starting cornerbacks Shawntae Spencer and Carlos Rogers from getting major playing time.
All signs point to Tarrell Brown and Tramaine Brock getting the start at cornerback, with rookie Chris Culliver also getting solid minutes as well. Philip Adams should also figure in to the game plan as well.
The unit will be tested by a Raiders receiving unit which includes Darrius Heyward-Bey, Denarius Moore and newly-signed tight end Kevin Boss.
With last year's nose tackle Aubrayo Franklin off to the New Orleans Saints in free agency, the 'Niners have done some shifting to fill the big gap left in the center of the defensive line. Former defensive end Isaac Sopoaga (pictured) and Ricky Jean Francois have slid into the nose tackle spot, while Ray McDonald and Justin Smith will most likely fill out the end positions. Ian Williams and Will Tukuafu will also be getting big minutes Saturday evening.
The line isn't fully set just yet, and it will be interesting to see how the line pressures Raiders starting quarterback Jason Campbell.
Saturday's game is a reunion of sorts for new 'Niners head coach Jim Harbaugh, who spent two seasons as the Raiders quarterback coach. In his first season with the Raiders, quarterback Rich Gannon was named MVP and the team went to the Super Bowl.
He will be going up against the Raiders' Hue Jackson, the former offensive coordinator promoted over the offseason when head coach Tom Cable was released.
How will Harbaugh react to coaching against his old team for the first time? How will the two new coaches carry the mantle of this long-lasting rivalry?