Sounds like you have more experience in this stuff than I do, . I've spent alot of time on it all though, probably too much. When it comes to eReaders I'm lazy: I just want to be able to throw an ebook on my reader and have it work perfectly right off the bat, no fuss, no muss, but it seems like I end up having to fight with almost every ebook I want to read, which I just don't have the time for anymore.

PDF's seem to be the biggest problem for me; they never look right on my Nook, with the way the formatting is. If I zoom out enough to see the entire layout, the print is too small to comfortably read, and if I zoom into a normal font size, alot of things just don't show up anymore, like some of the extra pictures, etc., plus like ya mentioned, there's alot of big blank spaces sometimes, and wierd formatting.

Nowadays, I try to get anything I want to read, already created as an epub, hoping that helps, which sometimes does and sometimes doesn't. Sigil is a really nice epub editor with one major flaw; the webkit used to render it is dog slow and can get unbelievably frustrating when it acts up. I've also used eCub, which isn't too bad. I just noticed this program that looks interesting too, but haven't used it yet.

I think the thing with calibre is it's just nice to be able to add tags, sort by author, sort by year, by series' and a butt-ton of other things, and all the books are shown in one list, with columns showing some metadata. Plus when you click one you can see a bunch of it's metadata, summaries, cover, etc. in the right window pane, and you can launch/read any book in the list by clicking it instead of having to open explorer find the folder ya want then run each book you might want to read. Plus the news sources really is pretty cool, especially how you can create your own. They're updating calibre, I swear, almost every time I start the program, so maybe by now you can do some of the stuff ya didn't like about it saving to disk. For instance, you could have it point to your Flash Drive with the folders on it, and just have Calibre use that as it's working folder so no new ones are created, it just uses those, and in the options you can tweak it to save the folder names exactly how you like them. Dunno if you've already tried the highlighted things below, but if not, it might be worth toying with: