There is no point in pretending this is quick to set up. Nor is it especially easy if you're not pretty clear on how your own AV equipment is connected and set up. The manual says to "allow 45 minutes". That seems about right to me (although it is now many years since I set up my very first Harmony). On top of that 45 minutes, you will probably make several more round-trips via your PC to fine-tune your setup to suit you just right (and a PC with an internet connection is COMPULSORY, please note.)
However, it is one of the best gadgets I own - if you are prepared to take the time and effort, the rewards are yours for years to come. This is my third Harmony (they've been around many years now). I would note neither of the previous two have failed - they both gave years of reliable service. Being heavily used, they just got a bit old and tired looking and I find myself looking at a new, shiny model! That means, over time, most of my AV equipment has changed as I went from video-recorders/analogue TVs to Freeview to Freesat, to DVD & then Blu-Ray, to a PVR and so on. So one of the things it may be useful to know is that the lengthy setup time was needed just once, all those years ago. I've long since worked out precisely and exactly how I want my buttons to react and changing one piece of equipment now only takes 5 or 10 minutes. For instance, I recently changed a dead DVD/HD recorder into a Freesat PVR. I think it took under 5 minutes to modify my Harmony. The buttons I use regularly I ensure are are all in the same place (for me, that's stuff like "Subtitles" and - especially - a 10-second rewind & a 30-second fast-forward). It also means my learning curve on a new piece of equipment is very brief, as my remote therefore works the same way and I know where the buttons are in my sleep. Even when I change Harmony, the button layout doesn't change very much, so I'm quickly up to speed. Every piece of equipment I've bought has been in the enormous Harmony database. Occassionally I have needed to "teach" the remote a single command, but that is quick and easy to do. Note that you cannot control a Wii, as that uses bluetooth for communication.
Not only does it allow you to replace all your remotes with a single one, the Harmony allows you to setup what it calls "Activities". I have a TV, a surround-sound, a blu-ray player, a freesat PVR and a Nintendo Wii all hooked up. Part of the initial setup encourages you to setup these "Activities". So, for example, when I want to watch recorded TV, one button press switches on the TV, surround-sound & PVR. Each piece of equipment is automatically set to the right input with that single button press (eg HDMI2 on the TV for my PVR). Then each piece of equipment is entirely controlled via the Harmony: volume buttons control the volume on the surround-sound whilst channel-change and record buttons control the PVR, and so on. All this is completely transparent in use - once set up correctly, it simply works for ever more.
The Harmony 650 is slightly bulkier than either of my earlier models, but is very light and feels very well-made. Button presses are distinct and clear (not like the "mushy" keys you get on some remotes). The button layout has changed slightly from my previous model but I think it is an improvement as different "sections" are more clearly grouped together and slightly separated now from one another (eg the bottom section - as always - is the numeric keypad. Next up Play, Pause, Stop, Rewind etc buttons are more logically grouped together. Above that, another clear group of buttons for the direction pad, volume up & down and volume up & down. It feels clearer and slightly bigger - an advantage for those of us who now use reading glasses! Incidentally, when you swap one Harmony remote for another, you simply select it on the PC and all your settings are transferred to the new remote. The 650 uses ordinary AAA batteries, whereas my last model used a rechargeable that came with its own "base station" for storage and recharge. If you prefer that, you might want to select a model further up the range. In the past I've found batteries last about 9 months. The buttons are backlit - when you pick the Harmony up, they light up which makes life easier if you like a darkened room for viewing. The LCD screen at the top is in colour - these are the main buttons for setting up those specific commands that suit the way YOU like to use your equipment. One thing to note if you're an existing Harmony user is that each "screenful" is 4 items not 6. I haven't found this a problem personally - it just took a little bit of re-arranging buttons to suit me. This remote can control up to 5 items - more expensive Harmony remotes can control up to 15 if you want (for example) to also use it for a hi-fi centre.
All in all, I'm as pleased with this Harmony as any previous model. Maybe even a little more so - it is very comfortable in the hands and the button layout feels a little better.
In conclusion, if you're prepared to spend the time at the beginning of your ownership, I'm certain that you'll be a Harmony fan too! If it feels too complicated or you don't want to have to spend the time, you will probably regret it. A little patience will go a long way and be well rewarded. I recommend this very highly.