Here are some considerations.
/Applications is ONLY used for programs installed when the OS is installed. Since I am the ONLY user on the system, everything goes into ~/Applications. So essentially, all non-OS data is on /Volumes/Disk2.
This allows a full OS resintall to be trivial. I was actually able to put this into practice recently. My 20gig OS drive experienced a hardware failure and Aqua could not come up at boot. I was stuck at the command line. I found out the disk was bad.
No problem. Put in a new disk, install the OS. After the final reboot I am logged in as "gary". The first thing I do is enable the root user and login as root. Once I am in, I simply launch Netinfo Manager and change my home directory to /Volumes/Disk2/Users/gary.
You will want to keep the original directory in /Users so you can see what the skeleton permissions need to be if you move a user later.
Once I change my home directory over while logged in as root, I just need to logout and login as myself and I have my original profile.
To make things easy I have a weekly cron job that backs up all my unix config files, such as /etc/hosts.allow, /etc/hosts.deny, /usr/local/samba/lib/smb.conf, etc. I even do a "crontab -l >> root.cron" so I save the contents of my cron files.
If you take great care, a system recovery becomes trivial.