Le'Veon Bell has returned as the centerpiece of the Pittsburgh Steelers offense at a time when starting quarterback Ben Roethlisberger is injured, which likely makes him an even bigger part of the offense against a stout Baltimore Ravens run defense this week.
Eddie Lacy emerged from Week 3 without any further damage to his ankle, and faces a 49ers defense that has allowed five rushing touchdowns in their last two contests.
Latavius Murray busted out last week and has a great opportunity for a repeat performance Sunday against a Bears defense allowing 4.7 yards a carry and a league-worst 35 points a game.
Melvin Gordon has the best matchup of his young career Sunday, at home against a Browns defense allowing 4.9 yards per carry.
Matt Forte should again be the focal point of the injury-laden Bears offense against an Oakland Raiders defense that allowed 118.0 yards on the ground in the first two weeks of the year before limiting Browns to 39 yards last Sunday.
Karlos Williams has scored a touchdown in every game this season and will make for a chic play if LeSean McCoy continues to be bothered by a hamstring injury.
Thomas Rawls proved his ability last Sunday and, if Marshawn Lunch is unable to play through a hamstring injury, could shine Monday night against a 20th-ranked Lions rush defense that has allowed five touchdowns this season.
Mark Ingram could find room to run on Sunday against a Cowboys team that allowed almost 200 total yards to Devonta Freeman last week.
Giovani Bernard out-touched and out-gained Jeremy Hill in Week 3, and faces a San Diego Chargers defense that has been middle-of-the-pack in yards allowed but has not given up a rushing touchdown yet this season.
Jamaal Charles is coming off the first three-touchdown game of his career, but he could have difficulty hitting paydirt Sunday on the road against a Bengals defense that has yet to allow a rushing TD this season.
T.J. Yeldon has solidified his hold as the Jacksonville Jaguars' running back, heading into a Week 4 encounter against the Indianapolis Colts, who rank 21st in rushing yards allowed per game.
Danny Woodhead should see more action Sunday after a quiet Week 3, facing a Browns defense that's surrendered 4.9 yards per carry and almost 400 yards of total offense a game.
Lance Dunbar might not repeat his career performance from Week 3, but Sunday night's game against a Saints defense allowing an awful 9.9 yards per pass attempt should still allow the lightning-fast back to make some big gains.
Matt Jones appears to have taken over the reins from Alfred Morris with 26 snaps (Morris had 12) in a loss to the Giants, though a goal-line fumble late in the game didn't do him any favors.
Jonathan Stewart will look to get on track in Sunday’s matchup against the Bucs after averaging fewer than 57 rushing yards per game in the first three weeks.
Jeremy Hill was out-touched and out-gained by competition Giovani Bernard in Week 3, but has a chance to bounce-back in Week 4 against an average Kansas City Chiefs rushing defense that allows 94 yards per game on the ground.
Joseph Randle scored three touchdowns early but shut down in the second half of Week 3 as Atlanta adjusted to a simple Dallas game plan, and it remains to be seen how effective he can be if the game plan doesn't open up.
Charles Sims caught the lone touchdown pass of the game last week and will look to bring his versatility against the Panthers on Sunday, who have allowed 61 receiving yards per game to opposing running backs.
Frank Gore finally made a significant contribution for the Indianapolis Colts last week and looks to sustain that momentum Week 4 against the Jacksonville Jaguars, who rank 12th in rushing yards allowed per game.
Alfred Blue is looking over his shoulder at Arian Foster, who is close to returning from a groin injury, but he should be the lead back in Week 4 against the Atlanta Falcons, who rank 15th in rushing yards allowed.
Carlos Hyde should see plenty of snaps against a questionable run defense, but he won't get many carries if the 49ers have to play catch-up again.
Adrian Peterson leads the league in rushing through three weeks, but faces a stout test in the Broncos sixth-ranked rush defense that has held two of its three opponents to less than 3.5 yards per carry.
Bilal Powell could be a deep sleeper Sunday if Chris Ivory remains on the sideline with a quad injury, as the Miami Dolphins are allowing a woeful 145 rushing yards per contest.
Andre Ellington is expected to return from a knee injury for Week 4, but he'll be facing a tough St. Louis defense, plus Chris Johnson may still be heavily involved.
Ivory is battling a quad injury, but if he can take the field, will face a Miami Dolphins defense allowing 145 rushing yards per game.
Devonta Freeman made the most of being the bell-cow back against the Cowboys, but will face a stiff test against the Texans, who haven't allowed more than 62 yards to an opposing running back this season.
Andre Williams led the Giants in carries and got the goal-line looks in Week 3, but squares off a Bills' run defense that has allowed just one score on the ground through three weeks.
Lamar Miller is dealing with a gimpy ankle and faces a New York Jets defense that is allowing just 13.7 points per game this season.
Isaiah Crowell had a quiet game against the Raiders in Week 3, but this week faces a struggling San Diego Chargers run defense that is 28th in the NFL in rushing yards allowed this season.
C.J. Anderson faces a Vikings run defense Sunday that's allowing almost 120 rushing yards per game, but until his lingering toe injury heals and the Broncos offensive line starts to provide better blocking, his production will likely remain limited.
Doug Martin will try to get back on track Sunday against the Panthers, though he may find that a tough task against a team that’s allowed 65 rushing yards per game to opposing running backs.
LeSean McCoy continues to fight through a hamstring ailment, and will face a New York Giants defense which is second in the NFL in rushing yards allowed this season.
Justin Forsett is only averaging 3.1 yards per carry through the first three games, and this week has a touch match-up against a tough Pittsburgh Steelers run defense that is in the top-10 in the NFL in rushing yards allowed.
Mike Tolbert will hope to keep getting 8-10 touches as the Panthers take on a soft Bucs front seven that allowed 186 yards to the Texans on the ground last week.
Marshawn Lynch's availability for Monday night's game due to a hamstring injury may not be known until it is too late to find other options, making him a risky play in Week 4.
Chris Johnson was fantastic in a Week 3 romp over the 49ers, but with Andre Ellington expected to return from a knee injury, Johnson could see his carries drop off by 50 percent or more.
Darren Sproles received 11 carries as the backup to surprise starter Ryan Matthews, but figures to see a reduction if DeMarco Murray returns in a tough matchup against the Redskins third-toughest run defense.
Reggie Bush could draw a surprising number of targets if he plays, but his inability to practice last week suggests he's no better than questionable to return from a calf injury.
Jacquizz Rodgers kept rookie running back Jeremy Langford on the sideline last Sunday, but is unlikely to see enough work behind Matt Forte to be considered an option in Week 4 against the Oakland Raiders.
Ronnie Hillman faces a Vikings defense Sunday that's allowed almost 120 rushing yards per game so far, but a struggling Broncos offensive line and a backfield time share with C.J. Anderson put a strong damper on Hillman's ceiling.
Alfred Morris saw just 12 snaps in Week 3, two weeks removed from a 25-carry, 121 yard effort in the opener, and now appears to be behind Matt Jones on the Washington depth chart.
Duke Johnson is the clear back-up to Isaiah Crowell as a rusher, but his activity in the passing game allows him to still be productive and this week he has a good match-up against a San Diego Chargers defense that is 28th in the league in rushing yards allowed.
Knile Davis failed to get a touch on offense last week as Jamaal Charles' primary backup, and now faces a Bengals defense that hasn't allowed a rushing touchdown in three games.
Todd Gurley was unimpressive in his NFL debut, and he'll likely split the workload with Tre Mason and Benny Cunningham in a game in which the Rams are heavy road underdogs to the 3-0 Cardinals.
DeAngelo Williams went back to the bench with the return of Le'Veon Bell, and even if he gets some spot duty in Week 4 he is unlikely to get enough work to thrive barring another Bell absence.
Tre Mason has to split work with Todd Gurley and Benny Cunningham, and the Rams may be forced to abandon the run in a road game against the 3-0 Cardinals.
Ameer Abdullah continues to work unsuccessfully in a timeshare and brings a 3.9 yards per carry average into a contest against a Seahawks defense allowing 3.7 yards per carry.
Ryan Mathews rolled up 128 total yards against a tough Jets defense in a surprise starting role, but would face an even tougher test against the third-ranked Washington run defense if DeMarco Murray remains sidelined.
Joique Bell is averaging 1.1 yards per carry while sharing snaps with two other running backs and faces a Seahawks defense coming off of a shutout in Week 3.
Rashad Jennings carried the ball just 11 times in a 32-21 win in Week 3 and squares off against the league's best run defense in Week 4.