I have to say J. Michael Straczynski's run from Amazing Spider-Man #471 (original numbering, printed as ASM Vol. 2 #30) to Amazing Spider-Man #545 was among my favorites for how radical it was. I could say this run is comparable to Grant Morrison's New X-Men in terms of how many changes it tried to bring and how few stuck around in the end. Nevertheless the effort is well appreciated.
Not seeing the classic villains was a nice change, as they had grown pretty stale until the Gauntlet and Grim Hunt revived interest in them, and I bet I am in the minority who considers the Ezekiel VS Morlun VS Totem Spider-Man stories ingeniously refreshing. I also feel Aunt May became a much stronger character thanks to JMS.
Those who are fans of JMS and his run in Amazing Spidey are welcomed to come discuss what they enjoyed most and where they would have liked the stories to go, had they not been retconned away by One More Day and Brand New Day.