At this point, with the sheer amount of data, I've structured things based on individual drives. All of my devices have the onboard SSD - I go for 1TB minimum. Call me old fashioned, but I still partition that one in two, one containing the Windows stuff and the essential 3rd party software, and a second partition which contains games, downloaded media, miscellaneous software, generally the stuff I use more frequently, but isn't vital. It's also where I store all downloads to keep the Windows partition clean and separate.

As for my external drives, I have one which I keep stuffed with game installs (2TB), and a second one which serves as my media library drive - music, movies, etc (1TB).

In terms of folder structures, I either use the default ones which come with Steam, for instance, or I keep it as simple as humanly possible (eg. Music > Artist > Album). Downloads are lumped in a single folder, wherein I may make subfolders for mass downloads of mods and such. Otherwise, Search & pray! With indexing turned off, because I like to hurt myself!

Edited to add sizes and: bought a second 2TB external which I plan on using as a back-up for my music library, some DRM-free games, and whatever movies may strike me as worth preserving.