I have the Harmony 650 and a Harmony One, both are great. The 650 you are looking at is a great little remote, you should find the basic set-up pretty easy, it controls up to 5 devices and a lot of activities, I am sure there is a limit on activities but I have not hit it.
In less than an hour you can have your 5 devices defined and chances are all of them will be in the Harmony database which means you don't need to go through the tedious process of teaching the Harmony the commands using your old remote. You'll also get 4 or 5 basic activities set-up, Watch TV, Watch Blu-Ray, Listen To... Now from here on it gets a little harder, at this point, depending on your gear and activities you will likely find you will need to tune up the command sequences, getting the correct source is one of the hardest things if the device you need to pick a source from does not have a direct source command, many don't, you hit source and get a menu that has no way to force it to a known starting point. Actually there is no great answer to that one, to make things truely smooth requires that you "work" with it a little, like make it a rule that you always put the source to a known spot upon exiting an activity (you tell the Harmony to do this and as long as you are properly in that activity, meaning everything is set right, you can for example, program it upon exit to open the source menu, cursor up twice, and hit enter. I have mine set to always going to STB on exit, so unless stuff gets messed up, it is always in a known state. (My receiver does pass-through HDMI when it is off so STB is a nice place to leave it anyway.)
Once you get all of that dialed in you will be pretty savvy on navigating the Harmony and tweaking things, then you enter the final phase, true elimination of the other remotes. This takes some time if you really want it to be easy in use, what I did was keep all remotes handy and anytime I had to struggle with the Harmony, like dig 9 screens deep for a command and had to use the real remote, I wrote down what I would need and then would go tweak the Harmony, they have a pretty cool app desktop or web based you use to adjust still, I prefer the desktop version as it is more flexible, the web version is easier.
The more you put into this fine tuning upfront, the more payback you get in frustration free automation, until upgrading my TV and receiver recently I had not touched one of the dedicated remotes in a couple years, don't even keep batteries in them, I keep a common set in the drawer with them all. However, don't bother unless you are willing to put in the effort, too often it is the Harmony that ends up in the drawer or worse, just adds another remote to your collection. I had no choice, the wife will only allow me cool toys if I can keep the operation of them within her reach. Also the wiz-bang factor is pretty high when you have company over