Having multiple programs that need access to the files can indeed be a problem. We had someone a while back who was using something that tracked academic citations, I think it was, who brought up the same issue (except that he was highly rude about it). There may be no practical solution, at least at the moment, than maintaining two sets of files -- one for calibre, and one for the other program.
I think we may get a bit too paranoid about space, though. I have about 2500 ebooks, which take up somewhat over 1 GB of space (admittedly a lot of them are fairly short; I need to start rounding up collections of short stories and packing them into anthologies). In some ways, I've never mentally moved past the PDP-11 days, with RL02 removable-pack drives that held a whole 10 MB each. True, it would take hundreds of pounds of disc packs (and several cubic yards of racks to store them in) to store my ebook collection, and duplicating that would require another room just to store the spares ... but I remind myself that I'm not working on a PDP-11 anymore, there probably isn't an RL02 left alive in the world, and the ebook collection that would have required over 100 of those big boys (for anyone who's never met one, an RL02 pack was "compact" at about 16" in diameter and 3" thick or so; it held several 14" aluminum platters) will now fit neatly on half of a SD card the size of a postage stamp, or about 1/10 of 1% of the 1 TB drive I was looking at on buy.com yesterday -- which would amount to less than a dime's worth of storage. So, despite that nagging voice in the back of my head saying "you're wasting space! WASTE! WASTE!" I've realized that actually, if I want to recover that space, I would do better to weed out crappy digital camera photos (I take a lot of pictures of my fish, for instance, which pretty much by definition means I have a lot of pictures of an empty part of an aquarium with a little tail off on one side) and have as many duplicates of my ebooks as I want. Or just go buy a 1 TB drive for $80 and not worry about space.
It's kind of crazy ... I remember, 15+ years ago, haggling with a vendor at a computer show to get a better price on a new hard drive for my computer. I remember the price because it ended up being $365 ... $1 per day of the year. For a 1.2 GB drive. Just about big enough to put all my ebooks of today on. Now I could get 4 TERAbytes of storage space for that much money. (of course, to even things out for getting drives so cheap, I now spend any/all resulting savings on video cards)
So, even a cheapskate like me can afford to spare a bit of drive space to let calibre keep its own files. If I really need the space, I could quit using World of Warcraft screenshots to take notes with, and if someone tells me something in-game that I need to remember (their email address, etc.) I could just, y'know, write it down. :-p
Sharing files with other people is easy, though -- a lot
easier, in fact, when you're dealing with books instead of files. Pop your device-to-share-with (a flash drive, let's say) into the computer, pick the books you want to share (and the format, if needed) and tell calibre to put them there. That way, instead of digging through multiple authors' folders looking for, say, all their alternate-history SF, you just click the "alternate history" tag in calibre, control-A to select them all, and send 'em wherever you need 'em.
The disadvantage to having a pointer to the original file is that the files could then be modified outside of calibre's control, which would confuse the heck out of its tiny little mind. The potential gains (people who need to allow other programs to manage/modify ebook files not needing to maintain a second copy of the files) would be far outweighed by the negatives (many more people making a royal mess of their files and pleading for help fixing it).
And I think I am now rambling so much that even I won't make sense of this when I've had more sleep, so I'd better stop now.
