Has happened to me on several occasions, especially with an older iPod shuffle. Synced in some music, then set everything I could find to "manually manage music" and "do not autosync". Moved the source files around on the PC, and the next time I connected the iPod, iTunes "helpfully" automatically wiped all the music off the iPod, since it could no longer find it in its library.

I've heard others getting burned in a similar fashion. One person needed to charge the iPod before a long flight, and didn't bother connecting the external drives containing all the music. Only after getting on the plane did he realize iTunes has "synced" his "empty library" and blown away everything on the iPod.