We go from the topic line “I put 2 hard drives in my computer, I want to block one" to the well thought out "I built a computer for a friend and he has kids and I want his personal hard drive not being tampered with when his kids use there hard drive.... How can I do this?" OMG this is funny.
I think that anyone would need a more clear description of your "Friend's" issue to give you a perfect solution. I can only assume that if the system is primarily there for your "Friend's" use, he has material all over the system drive( C: Drive, The Drive where the operating system and Program installations reside.) Following that assumption, this wouldn't be a situation where he could just take every thing with him on a portable drive. The C: drive must stay put and any user will have some interaction with it because the files that make Mr. Computer walk and talk live there.
If you are using Windows 2K, XP(any flavor), or Vista the simple answer is to set up an account for kids that has limited access, customized so they can do what they need without viewing/tampering with your "Friend's files.
If the situation is more like what most of these posters are guessing, your "Friend" wants to hide and\or restrict access to files from other users without that other user really knowing that they have limited access. In that case your "Friend" can use encryption software as noted in other replies, but what your "Friend" really needs to do is practice good file management. Keep all sensitive files in specific folders, use windows or 3rd party software to set permission to access and hide those folders. Back those folders and files up to disc routinely.
Good luck to you and your Friend.