The trade for Rob Johnson.
If you look at all the QB classes from 1995 (when they took Todd Collins in the 2nd round as the heir apparent to Kelly), there was an incredible lack of any QB talent in the next 5 drafts. I mean seriously, look at the list:
http://www.pro-football-reference.co...B-1980-now.htm
So there literally was nothing they could have done (outside of Manning, but that wasn't an option), and it can be chalked up to bad luck with the timing of Kelly's retirement.
However, in 2001, the Bills had the chance to grab Drew Brees, but instead took Nate Clements. Why? Because they had made the trade for Rob Johnson and he was the starter.
That, IMO, is the #1 thing that set the Bills on their current path to misery. It's not the only thing, and they should have recovered many years ago, but again IMO this cut so deep that they never have recovered. Can't win without a QB and they haven't had one since Kelly.