First, the Open With plugin is great for opening books in external viewers. Just download it and play around with it. You'll thank us.
Second, it sounds like you're talking not just about viewing books, but editing them. Let me outline my process for cleaning books. Maybe it will give you some pointers.
1. I import the book I need to clean into my "Working" library. Convert to htmlz. Save to file. Delete from Working library.
2. I unzip the htmlz file, producing an index.html file, cover, and auxiliary files.
3. I clean the index.html file by hand using Notepad++ and a couple of other tools. This process can be tedious, but it's the only way I can be sure it's right.
4. I import the index.html file into my "Main" library. I fix the metadata, import the cover, etc.
5. I convert it to Epub format.
The nice thing about this process is that by the time it goes into my final library, I've already confirmed that it's exactly the way I want. No messing around with different versions of books, etc. If I need to convert it to Mobi or other formats, it's already nice and clean so there shouldn't ever be a need to do any post-conversion work on it.
Also, my process automatically creates backups at every step. I have the original file that I can always convert again if everything falls apart. I have the htmlz file that I can unzip again if I screw up in editing. And I have the cleaned html file, which I put in a separate "Library" folder on my hard drive as a kind of archive in case I discover later I need to do some more cleanup.
I wouldn't recommend trying to do your editing on the book inside Calibre's library. Do it all externally, and it will probably work a lot better.