With the newer versions of calibre, for sure, you can do this easily via command-line, if you're comfortable with it - all you need to do is:
ebook-meta.exe book.ePub --cover coverImage.jpg
As far as I know this doesn't muck around with any internal formatting. You can use ebook-meta to update any metadata - title, author, series, cover image, etc.
Personally, I love the calibre command line tools, and hate the GUI
It is so much easier to type: "ebook-convert mybook.lit .ePub" to convert form a lit to ePub, or between any two formats. Any of the options you see in the GUI are available via command-line, and I actually ended up creating a small script that calls ebook-convert with my favorite options.