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Separate Data from System and Applications
Dedicate one drive for your system and applications (boot drive), and a separate one for your data. That way if the system drive fails your data is intact, and if the data drive fails, you can still boot up, and then restore to a new drive from backup. A double headache comes from mixing the two!
Shown at right are the Boot volume and Master volume that I use on my system. The Boot drive is actually a triple-SSD RAID-0 stripe, and the Master volume is actually a triple hard drive RAID-0 stripe.
The Mac Pro is ideal for a multi-drive setup; other Macs are limited to 1 or 2 internal drives at most (“dead end Macs”). While external drives can be used on such Macs, they mostly offer severely impaired performance relative to an internal drive. Performance and reliability are other considerations.
Avoid mixing data with system and applications
Avoid putting your data (images, spreadsheets, documents, music) on the same volume as your system, and preferably not even on the same physical drive as your system (eg a partition on the same drive as the system).
Therefore, one must have at least two drives to do it right, though you can partition one hard drive into two volumes as a half-way solution.
By putting all your data on one data volume (I call my data volume), you can backup just that drive (and perhaps your home directory too).
The separation of system and data generally means better performance as well, since there is no contention between software and applications for access to the hard drive. Also, less total data is stored on each drive, so the fast part of the drive gets used.