It's my understanding that the HKEY_USERS hive is broken down in to individual sub-keys with each user profile having its own sub-key. If no additional profiles have been registered, Windows is programmed to show a “default” sub-key inside the HKEY_USERS tree. This is the overriding profile when no other accounts have been setup, and should be treated with caution. A bad edit or deletion could conceivably prevent Windows from operating correctly or not at all.
Another consideration is besides there being a list of settings under HKEY_USERS, you’ll also find an exact replica or duplicate in HKEY_CURRENT_USER. This is necessary so that when you login, your user profile is taken from HKEY_USERS and copied in to a new table for easy access via the registry. Don’t be misled by the term replica or duplicate, though. The data stored in the HKEY_CURRENT_USER table is actually a live reference mapping to the very same information that is stored in the HKEY_USERS hive. Indiscriminate editing/deleting of HKEY_USERS will therefore affect HKEY_CURRENT_USER, and vice versa.
According to a lot of posts on this Forum by people a lot smarter than me, Windows 7 doesn't need any registry tweaking. It's able to handle the registry just fine on its own. It's not a question of if editing the registry will cause problems but when.
Having said that, a lot of folks here recommend CCleaner and its built in registry cleaner. It's not too aggressive and has a good track record. Especially if you take advantage of its ability to save the current registry before doing any cleaning. Additionally, it wouldn't hurt to make a current restore point or even better a system image before editing the registry.