Concussions have made at least one unavailable for Monday night's matchup at Candlestick Park between two of the league's toughest defenses.
San Francisco (6-2-1) and Chicago (7-2) lead the NFC West and North, respectively, and seem destined for the playoffs. The 49ers are hoping to go one step further this time and reach the Super Bowl, while the Bears were stopped one game short the previous season.
Those aspirations have been dealt a few major blows, specifically to the heads of Smith and Cutler.
Smith was hit hard twice in last week's 24-all tie with St. Louis, leaving the game in the second quarter after overcoming blurred vision to throw a 14-yard touchdown pass to Michael Crabtree.
Smith practiced again on Saturday, however his availability is still uncertain. He still hasn't been cleared to play by doctors, and the 49ers might not get a final verdict on his status until hours before Monday's game.
''Alex is still going through the protocol right now,'' offensive coordinator Greg Roman said Saturday. ''And that's in the doctor's hands. When we know, you will probably know.''
The Bears believe Cutler's brain trauma came on a helmet-to-helmet hit by Houston's Tim Dobbins late in the first half of last Sunday's 13-6 loss. Dobbins was fined $30,000 earlier this week.
Chicago announced Friday that Cutler wouldn't play this week, meaning Campbell is slated to start.
The Bears brought in Campbell in the offseason just for a situation like this after Cutler broke his right thumb late last season and Chicago went 1-5 without him to miss the playoffs.
Campbell completed 11 of 19 passes for 94 yards in relief last week, his first extensive playing time since a road win over the Texans with Oakland in Week 5 of last year. He's started 70 games over the past six seasons, and has 70 touchdowns compared to 50 interceptions.
"He's comfortable in the pocket, comfortable calling the plays," center Roberto Garza said. "Look at his track record. That speaks for itself. There's a reason why he's here, and there's a reason why he's in the situation he's in.
"He probably should be starting somewhere. He's that type of player. Unfortunately, we're in this situation, but he's gonna step in there."
Campbell has completed 51.0 percent of his passes for 239 yards with one touchdown and two interceptions in two meetings with the Niners, both resulting in losses at San Francisco with Washington and the Raiders.
While Chicago may be turning to a veteran backup, the 49ers may be giving Kaepernick his first start.
A second-round pick out of Nevada in the 2011 draft, Kaepernick's most extensive action came after Smith went out last week. He went 11 for 17 for 117 yards, while rushing eight times for 66 yards and a touchdown.
He is approaching as if he will start against the Bears - the same way he prepares every week.
"Same reps as always. Nothing really changes," Kaepernick said. "I've always been out there preparing myself to start."
Kaepernick's running ability gives San Francisco a different dimension than Smith offers, but the Bears' defense is fifth in the NFL, and excellent against the run, allowing 92.3 yards per game.
Overall, Chicago gives up an average of 307.3 yards, and the unit leads the league with 30 turnovers and 19 interceptions. The Bears picked off Houston's Matt Schaub twice last week and held the Texans to a season-low 215 yards.
The Niners' Frank Gore will try to continue his success against the Bears. He's totaled 215 yards and a touchdown on 37 rushes while the teams have split the last two meetings.
San Francisco took the most recent matchup 10-6 at home on Nov. 12, 2009, when Smith and Cutler faced off on national television.
Another defensive struggle is likely since the 49ers are also among the best in the NFL, ranking third while allowing 292.1 yards per game - 196.8 through the air.
They've also shown the ability to get to the quarterback, getting eight of their 17 sacks in the past three games.