These are some suggestions, hints and tips on how to setup Quake to give you a good experience.
Launch Quake and press the ^ key (left to the 1), you now see the console. Here you can enter countless commands and set variables.
Everything you enter in the console you could also write into a config file so it will be loaded when you run Quake again. TODO config.cfg/autoexec.cfg explanation, new page?
I cannot look with the mouse!
+mlook in the console to enable mouse-look
There is no crosshair!
crosshair 1 in the console to enable the crosshair. Some engines bring more crosshairs, try "crosshair 2" and other integers.
I am walking to slowly!
Set "Always run" to "On" in the Options Menu to set a faster walking speed.
How to disable the auto-aim?
sv_aim 1 (yes, 1) to disable the automatic vertical aim.
I cannot figure out how to run this map!
If you want to be able to play a lot of fan-made singleplayer maps easily, check out the Quake Injector
More advanced changes
Disable texture filtering
To enable oldschool pixel rendering in instead of the texture blur enter
gl_texturemode GL_NEAREST_MIPMAP_LINEAR in the console. Oh, doesn't it look great now!
You can also make particles be rendered as squares instead of circles by entering
r_particles 2 in the console, not many engines support this. Fitzquake and Quakespasm do.
Faster rising underwater
Add this to your config and change mouse2 to whatever key or button you use to jump to enable faster ascension underwater when using the jump key.
alias +movejump "+jump;+moveup;" alias -movejump "-jump;-moveup;" bind mouse2 +movejump