So it seems that Registry junk is a Windows fact of life and that Registry cleaners will continue to have a place in the anal-sysadmin’s tool chest, at least until we’re all running .NET applications that store their per-user settings in XML files – and then of course we’ll need XML cleaners.

To summarize his post: Mark details some of the problems that the Windows Registry has, especially with lingering keys from software uninstalls. Mark points out that sometimes a lingering key can get in the way with proper function of some software. This can be diagnosed with Mark's RegMon tool, to see exactly what registry entries are in play when a problem occurs. Then, one can use whatever tool they prefer to clean out that problem entry.

So, if we take Mark's guidance, we're back at the point where registry editor's and cleaners can be appropriate for solving specific problems, but the offer little benefit for speed increases.

It's worth noting here that tools like CCleaner offer to clean up things like temp and cache directories and pre-fetch files as well as the registry. Those options should have more effect than their registry cleaning tools.