Time ago, for a customer, I created a plugin that integrates the thumbnail generation system of WordPress. The needed was to “force” WordPress to generate always a thumbnail with the exact sizes, while it usually returns the best fitting thumbnail it can find within the already generated ones.
Yes a theme can register many thumbnail versions but if they change the new format are not generated for old images in the media gallery. More, the use of thumbnail via programmatic call to the thumbnail generation function, does not require to have them already stored in the upload folder (that consumes space as well!).
Such kind of thumbnails can be generated on the fly and cached in a cache folder, leaving the upload folder cleaner and the media database lighter. A separated cache folder is even important since you can avoid to back up it.
All that is done by Thumbnails, my plugin just released to the community.
Thumbnail is a very light plugin and does not change the contents or the behavior of you blog. If you deactivate it everything return as before the first installation (eventually just the cache folder could be deleted).
When firstly installed it has no options activated so you have time to play with the configuration panel before having it to start to generate the thumbs.