Backups ..or generically tarballs/zips/..etc. There have been way too many times I've had to split zips/tarballs etc just to copy over stuff over a fat formatted usb disk. Of course I no longer do that but there was a brief period when this was a problem.

I remember back in Commodore days, ARC or LHARC, or one of the archiving programs had the ability to span 1541 disks. But I can't remember why that was necessary. Under what circumstances was I moving files around that were 3x the size of the computer's memory?

Good question. Even for programs and games that spanned multiple disk, you’d explicitly arrange the data so that it makes sense (sometimes even duplicating some of it), and not just uniformly spread it across all the disks.

I can’t remember a single instance where there was the concept of a file that spanned multiple disks on the C64. In theory, the hard drive add ons might have lead to the use of such files (they don’t have to fit into memory at once, you can just seek within the file), but given their relatively low popularity, that was probably very rare, if there was any support for such files in software at all...

Wish there were a FUSE for windows... I mostly format external drives as NTFS as it's easier to get support on mac and linux than anything else in windows.

Scientific datasets, for one.