Harmony has a centralized database with the IR commands for each device. In some cases the device (tv e.g.) supports commands that were not designed into the remote control. If for some reason one of the oem remote buttons are not available via the harmony database - or if you have an odd device that may not be in the database at all - then you can teach the harmony the commands you need from the OEM remote.

The only way a harmony wouldn't work is if the device is RF or if the device isn't in the harmony database and you don't have the OEM remote.