Colin Kaepernick has struggled in the 49ers' last two defeats.
The short week does not give Harbaugh and his coaching staff much time to sort out and fix the problems that have plagued the 49ers. Both of these teams have a 1-2 record, but the Rams are not to be taken lightly.
In their games last year, the two teams played to a 24-24 tie, then the Rams defeated the 49ers, 16-13.
Jeff Fisher, the head coach of the Rams is known for building tough, physical defenses, but the Rams have allowed 89 points in only three games. Offensively, the Rams are a work-in-progress, as they are trying to replace former stars Steven Jackson and Danny Amendola.
The 49ers are battered and bruised as several key defensive players are likely out. Unlikely to play are Patrick Willis, Ian Williams and Nnamdi Asomugha. Offensively, Vernon Davis has been battling a hamstring injury, and his status is uncertain.
In addition, Aldon Smith is out indefinitely, as he fights to regain control of his life.
The 49ers came into the season already missing Michael Crabtree, Mario Manningham and Chris Culliver, so the loss of these additional players against the Rams is a huge hurdle.
If the 49ers hope to be in the thick of the playoff race, this is a critical game for them. Let's take a closer look at some of the key matchups that will determine the outcome of the game.
*All individual stats are courtesy of Pro-Football-Reference.com. Team stats are courtesy of 49ers.com and stlouisrams.com.
Anthony Davis and Chris Long battled in 2012.
Davis and the 49ers' offensive line will need to keep the Rams' pass rush off Colin Kaepernick. Long led the Rams in 2012 with 11.5 sacks.
This matchup will likely be a microcosm of the game. If Davis can keep Long at bay, the 49ers offense will have a good chance to move the ball.
Joe Staley was selected to the Pro Bowl in each of his last two seasons.
On the left side of the 49ers' offensive line, Joe Staley will battle Robert Quinn. Staley has been a Pro Bowl selection in each of the last two years, but he will have his hands full against Quinn.
Quinn is in his third NFL campaign. He is strong, fast and plays with a mean streak. In 2012, he accumulated 10.5 sacks, second on the team to Chris Long.
Together, the tandem of Quinn and Long racked up 22 sacks last season. Their success fuels the Rams defense.
Staley can sometimes have trouble with very fast edge-rushers. He will need to be at the top of his game to stop Quinn from wreaking havoc.
Daryl Richardson is the Rams' leading rusher.
The San Francisco 49ers defense will be without two of its best players against the Rams. Patrick Willis and Aldon Smith are both out. Their absence could enable the Rams to run the ball, something they have not done successfully this season.
After three games, Daryl Richardson is the Rams' leading rusher with 98 yards on 30 carries.
The 49ers have surprisingly had trouble stopping the run in the past two games. They allowed 172 yards on 47 carries to the Seattle Seahawks. Marshawn Lynch controlled the tempo of the game, as he rushed for 98 yards on 28 carries.
Against the Indianapolis Colts, the 49ers allowed 184 yards rushing on 40 carries. Ahmad Bradshaw led the way with 95 yards on 19 carries. The Colts were able to control the game in the second half with their running game.
The 49ers cannot allow the Rams to establish a running attack and control the game.
The 49ers defense was unable to contain both the Seahawks and the Colts. If the defense allows Richardson to have a big game, the 49ers will be in jeopardy of losing their third consecutive game.
Dan Skuta will replace Aldon Smith for the foreseeable future.
The San Francisco 49ers acquired linebacker Dan Skuta primarily because of his special teams play. They did not expect him to be starting at outside linebacker.
There will be a huge drop-off in speed, explosiveness and big-play ability without Aldon Smith. Nothing against Skuta, but Smith is one of the elite players in the league.
Skuta will go up against the Rams left tackle Jake Long. After five seasons in Miami, Long joined the Rams as a free agent. Long is one of the best at his position, with four Pro Bowl selections and one first-team All-Pro honor.
Skuta is unlikely to have much success, so any contributions from him on the field will be important to the 49ers.
Frank Gore had his best game of the season last week against the Colts.
Frank Gore was rolling last week, when suddenly, offensive coordinator Greg Roman and head coach Jim Harbaugh seemed to forget all about him.
Gore had his best game of the year, with 82 yards on only 11 carries. Most of that came in the first quarter on the 49ers' only scoring drive of the game.
The 49ers went away from running the ball and tried to pass, which was not successful.
The Rams rank 16th out of 32 teams in rushing defense. Through the first three games, they have allowed an average of 105 yards on the ground to their opponents.
In comparison, the 49ers rank 29th, allowing 139.7 yards per game on the ground.
With the injuries to the San Francisco defense, it would be tremendously beneficial if the 49ers offense could control the ball and the clock.
The 49ers are having problems in the passing game because their receivers are having trouble getting open. Tight, press coverage has stymied the passing attack, and you can expect to see a lot of that from the Rams' defense.
This makes it critical for the 49ers to be able to run the football. Frank Gore and the 49ers ground attack will play a major role in determining the outcome of this game.