What works

Nearly everything, including USB MIDI keyboard.

As other reviewers have mentioned, Synthesia does not actually play MIDI files but instead relies on a local MIDI synthesizer to do the actual sound generation. The easiest way to do this is with Timidity by running this command prior to starting Synthesia:

timidity --realtime-priority=100 -iA -B2,10 -Os

Upon startup, ensure Timidity is selected as the output source. If you're using a USB MIDI keyboard, ensure this is selected as the input source.

Note the -B2,10 option. Make the 10 lower to increase performance but lower sound quality. Make it higher to increase sound quality but lower performance.

It's also possible to use the Jack sound architecture to take advantage of low-latency sound cards and improve sound performance, but since all I have is an onboard sound chip, this was not tested.

Keyboard testing was done with an M-Audio Keystation 61es, but any MIDI keyboard supporting the standard USB interface should work just fine.

What does not

The game "requires" graphics acceleration, so depending on your graphics card, and the quality of its driver, performance may be great, sluggish, or non-existent.

I have a Radeon card, and the open source driver doesn't support acceleration, so performance is so slow as to make the game unusable. The proprietary driver supports acceleration, but it's far buggier, and will often freeze in a black screen upon startup or occasionally crash my entire system. However, when it works, play is responsive and flawless.

The game supports two video modes, DirectX and OpenGL. Unsurprisingly, the DirectX mode was far buggier and slower than the OpenGL mode. I recommend setting the game to OpenGL before starting it by setting the registry value to "opengl" (just search the registry with regedit for "Synthesia" to find all registry options.

What was not tested
Nothing.

Additional Comments