I know this is an unpopular opinion, as Resident Evil 4 is near-universally beloved, and personally it's probably one of the 20-or-so best games I've ever played. It's probably still my favorite third-person shooter game.
That said, I'm still heartbroken that Resident Evil 3.5 was cancelled. The initial version of RE4 that they showed, with the black fog and the castle and Leon being infected, is probably my most-wanted game ever. It looked to be the ultimate RE game, the culmination of the long-running story and a continuation of the dark, gritty stylistic approach that REmake and RE0 had. I was crushed when they scrapped it in favor of more action and less horror, and despite the final game being a masterpiece in its own right, it was never the RE4 that I wanted.
It hurts more because of the direction of the series since then, and the direction of the survival horror genre as a whole. Had that game come out instead of the final RE4, how many more "traditional" RE games would we have gotten? What would the series look like today? What about its contemporaries, Fatal Frame and Silent Hill?
Maybe RE 3.5 would have been crap and what happened was for the best, but the tragedy is never knowing what might have been. Put it this way -- in my mind's eye of everything that I hoped that game would be, nothing that's come out since has approached that potential.