We have been using the Harmony for several years now.
Setting up was a bit difficult, mainly because our Panasonic projector has a difficult set of commands. The support from the help desk was great, though. They solved all my problems.
All my other stuff (Sony DVD/HDD recorder, JVC receiver, Samsung digital decoder) was almost plug-and-play.
Even guests who stayed in our house could control all of our equipment without trouble. You just have to trust the remote: it thinks for you, so stop thinking about your equipment yourself.