You should never need to touch the "Program Files" directory. In fact, you shouldn't really mess with any of the OS directories, it would only cause problems and there's no real benefit. That said, I've personally been using multiple partitions/hard drives in my systems for the past 12 years without issue.
What I do is first create a partition for my Windows install... for windows 7 this partition was typically around 100 gigs. How on earth some people on here say they can get the OS to run on a 40gb partition WITH their programs installed in the Program Files directory is completely beyond me. I just yesterday did a clean install of windows, and the OS (Windows Pro x64) is taking up 67.5 gigs of space AFTER I've moved out all of my "My docs", "My videos", "My Pictures" etc. to another drive all together.
Application Data which should never EVER be moved, simply grows and grows every time you install new software and if you're a designer like me (videogame design), Adobe Creative suite, 3D Studio Max and every other program takes up a lot of space in AppData. Another thing to keep in mind is that if you let windows automatically manage your page file (virtual memory) it defaults to a size on par with the amount of ram you have installed in your system. In my case I have 24 gigs of ram so the page file - 24567mb (23.99gb) takes up another huge whack of space.
This time however, I dedicated an entire 500gb hard drive to the windows partition as I noticed that after about a year, the OS gets really close to the 100GB mark and I figured it'd be nice to dedicate a single HD to the OS and the 500gb was the smallest drive I had.
Like I mentioned above I have several other drives for all of my other files and software. I have an E drive (Extra) for random data that I want to sort at another time, an F Drive for Storage (My Docs, Pictures, Downloads go here), a G drive for games (Steam alone is 161GB) H drive for programs (This is where I manually install absolutely everything from Winamp and DivX to Adobe Master Suite and 3ds Max) and finally an M drive for Media where I put all Music, Videos etc. (which means I point My Videos and My Music here)
Not only does this make things a lot easier for when I have to re-install my OS (Simply nuke the C drive and re-install) but it also means that I NEVER have to worry about loosing any of my software related files (max saves, game saves, music, videos etc.) in an OS Crash or Virus situation and I don't have to worry about program stability as someone else here pointed out with a directory that uses a space in its name "Program Files" (one of my 3D apps crashes constantly if installed here). Of course I still backup all the important files to other media but I imagine everyone does.
The downside is that if I do re-install windows I have to re-install virtually all of my software (the rare program like Steam will simply run regardless of whether or not they're in the registry) but unless you're ghosting your HD or creating a backup image, you're going to have to do this anyway - and since all of my non-software related files are safe on separate drives, it usually only takes me a single day to get back up and running and I'm fairly sure I have a LOT more software installed than the average user.
Bottom line, its perfectly acceptable to have Multiple partitions or even drives for your software and leave the OS on a separate one and quite frankly after 18 years experience with computers and 12 years using this method, I wouldn't recommend anything else.