Gore, the franchise's all-time leading rusher, epitomized the team's highs (three straight NFC title games with a Super Bowl appearance) and lows (seven non-winning seasons) as a constant for a power running attack.
But now that he's gone, having signed a free-agent contract with the Indianapolis Colts, who is left to pick up the slack for the Niners?
"It's going to be different without Frank," quarterback Colin Kaepernick admitted Friday, closing out the team's first week of offseason workouts. "Frank was a huge asset to us, but we have a lot of great running backs here.
"We have Kendall [Hunter] coming back, who a lot of people forget about. Carlos [Hyde] had a great rookie year for us, and we'll probably be using him a lot more this year. We've brought Reggie [Bush] in, who's another great weapon on offense."
Gore, a third-round draft pick in 2005, ranks 20th on the league's all-time rushing list with 11,073 yards, on 2,442 carries, and the five-time Pro Bowler is one of 11 players in league history with at least eight 1,000-yard rushing seasons.
That's a lot of production to replicate, and that's just carrying the ball.
For comparison sake, Hunter, who is coming back from an ACL injury and missed all of last season, and Hyde have a combined 1,535 career rushing yards, with Bush, who entered the league a year after Gore, rushing for 5,465 career yards.
The three backs, though, have different skill sets, with Hyde more the between-the-tackles runner, Hunter the off-tackle speedster and Bush the pass-catching back, as evidenced by his 466 career receptions, as opposed to Gore's 342 catches.
"And those are just to name a few of the guys that we have back there," Kaepenrick said. "[Gore will] be missed, but we also have people that are more than capable of filling that void."