In case you're not familiar with them, the Harmony remotes are renowned for offering (relatively) easy programming via desktop software, which is available for both Windows and Mac systems. Just choose your home-theater hardware from an extensive (and frequently updated) database, then set up your desired activities ("Watch a movie," "Listen to music," and so on). The remote's built-in help screens walk you through any problems that may crop up (like the TV turns on but the receiver doesn't).
I've used several Harmony remotes over the years, including this one, and they've largely been outstanding. My only gripe with this model is that it doesn't use rechargeable batteries. But for 50 bucks it's absolutely impossible to beat. Don't take my word: Check out CNET's favorable review of the Harmony 550, and be sure to browse the user reviews as well for more real-world testimony.