I've wrestled with this for DECADES!

I've built software with a configuration database (Windows registry) and with flat configuration file-folders (*nix). I feel like I'm running in a circle because the trade-offs are so equally balanced that there's no best-case. From considering backups and database consistency, to tripwire malware detection of changed settings, to automation of access, to consistency in naming, retrieval, and type conventions, to self-documentation, to backwards compatibility... At this point I'm not even sure I would understand the correct or "best" methodology if it was handed to me on a silver platter.