It’s critical to have a good strategy for backing up your Plone database and compacting the object database.
The easy answer to the question "What should I back up?" is "everything." Backing up the Zope database file alone is not enough. It can be very difficult to reproduce a working configuration, complete with custom settings, Python libraries, and add-on products, when pressed for time. So, make sure that you always have a good, up-to-date backup of your entire Zope/Plone instance.
That said, the Python and configuration file components of a production installation typically change very infrequently, while the object database may be changing every few seconds.