Oh the memories ... "Do I really need a mouse driver? CD-ROM? What about Midi? Can I afford to load 'keyb' to change the keyboard language?". Not everything could be moved into the higher memory area, some games would not start when that program was used.
One of the thoughest games was Turrican 2. Everything had to be turned off.
The whole thing is a lot easier in DOSBox which replaced most DOS drivers with "native" access (of course emulated, but not loaded in the memory available to the DOS programs).





A real pain are the late 90s windows games that would change the resolution of the desktop instead of opening a new instance. Also ddraw games can be very annoying if they change graphics mode when entering the main menu / game (Jedi Knight's Sith enigne being a nerve wrecking example) or games that have the possible output resolutions hard coded into their .exe file.
The early days of 3D gaming were very experimental.
Some games would use the sound card as clock generator, so in order to play them, one had to go into the Windows system settings, dxdiag and disable sound acceleration.

Some .ini tweaking these days is a minor inconvenience compared to the experiments, tweaking, driver replacing and other work we had back in the days when running the games on the systems they were designed to run on.
It's only more complicated if these games use systems that had been abandoned or are inaccessible, when Microsoft decided to lock direct hardware access, which basically made Creative Labs AWE and EAX3+ useless and also prevented some 3D functions from working. GOG did and still do their best to find solutions for these problems, but one can't expect them to solve every little boo-boo. One interested in retro gaming must not be too lazy or scared to do some tweaking.