Wow! I think it ultimately depends on the scoring for your league. Depending on if it's a points league or yardage league, or a combo of both. I would mos tlikely avoid Holmes with the number 1 pick, but he's still a first rounder. With Larry Johnson around and the concerns about Holmes health, they'll probably lessen his work laod a bit. Though he'll still be a stud. Most likely you can't go wrong with Williams, Portis, Tomlinson, or Faulk.
As a side note, I'm in a keeper league in which I get to pick 2 players from my roster last year that were picked after the 4th round. (That way all of the "studs" are thrown back into the talent pool for the draft). So, of the players I drafted after the 4 round last year I have Portis, Vick, Randy McMicheal, and Donte Stallworth. I'll probably keep Portis and Vick and then go RB and WR with my first two picks. But, it's awful nice going into the draft knowing I've already got 2 horses on my roster.
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