To answer your question, is it reasonable to format with NTFS or exFAT?
Like you mention, this depends entirely on what kind of Operating Systems are going to be looking at this drive. If you are talking about Vista+ then NTFS is just fine. While other OSes (non Windows) can read NTFS drives, I'm not sure their support is as good as FAT32.
exFAT was recently added to the mix as a way to workaround some of the limitations of FAT32.
There are some other considerations as well. Windows 7 has support for BitLocker ToGo which allows for full hard drive encryption and mounting using a simple password. It's Read/Write on Windows 7 and then read only on Vista and XP and there is no cross platform support.
If what you need is lowest common denominator, I would go with FAT32 and deal with the limitations. If you are just using Windows XP+ then NTFS. If you are using Vista+ then exFAT.