The Colts are off this week and next play Monday night, Nov. 1 against Houston.
Clark is the team's third-leading receiver with 37 catches for 347 yards. Clark creates matchup problems, and even when he's not the target he helps dictate matchups and coverages that can be favorable elsewhere.
The return of receiver Anthony Gonzalez, out since the opener with an ankle injury, could help soften the blow a bit.
But when the Colts use three or four receivers, defenses are more comfortable using extra defensive backs. Against Clark, they have to decide whether to try to match his speed with a defensive back or match his physicality and size with a linebacker.
If he's out long-term, it's one of the biggest blows the offense could suffer beyond Peyton Manning going down.
The Colts are already dealing with the long-term losses of Bob Sanders and Melvin Bullitt at strong safety. Running back Joseph Addai hasn't finished the team's last two games with neck and shoulder injuries.