Kevin Kolb, who replaced Skelton in the opener and helped the Cardinals start 4-0, is out indefinitely with rib and chest injuries sustained Sunday when Arizona was beaten at home by Buffalo 19-16 in overtime.
Now Skelton steps in to lead the Cardinals to Minnesota to face the Vikings on Sunday -- and try to figure out how to succeed behind an offensive line that allowed Kolb to be sacked 22 times in the last three games.
"It's too much of a big deal," wide receiver Andre Roberts said after Wednesday's practice. "You know we had John at the beginning of the year, we had him in camp, so it's not like we're bringing somebody in new that we haven't played with.
"John's been here for a while. We understand what he brings to the table, so it won't be that big of an adjustment."
Last Sunday was the first time Skelton had been active since the injury -- and the rust showed. But Skelton said having a full week of practice with the starters will help him get back into the proper rhythm.
"Instead of just mentally repping everything like you do when you're the backup or inactive or what have you, you get to run it," he said. "You get to see against a defense. You get to experience it out there. It just makes the week go by that much easier because you are more comfortable with everything, and then come Sunday you are ready for everything that comes."
Skelton found it difficult to watch Kolb do the job he had fought for and, briefly, won.
"It's frustrating more than anything," Skelton said, "to put in all the hard work in the past years and offseason, getting named the starter the way I was, and then kind of have it disappear and taken away from you that early."
Copyright 2012 by The Associated Press