For me it was Freaks and Geeks. A short-lived dramedy about group of unpopular misfits dealing with high school in the 80's. It was swiftly cancelled by NBC in 2000 halfway through the season. NBC didnt know how to deal with a show of this calibre. It had critical acclaim, but the constant non-promotion of the show, pre-emptions and schedule changes hurt the ratings. It never really had the chance to find an audience. It remains, for me, one of the greatest shows ever. It had huge potential. Thankfully, the complete series was released on DVD with the original music intact.
It was the saddest cancellations ever for me. That and Sunset Beach (another NBC show - but that's a whole other story).
