What is the best way to get from Frankfurt (or Mainz), Germany to Prague, Czech Republic? Train? Or Aircraft?
First define best - do you need fastest, cheapest, most convenient, etc. Best has little meaning by itself. If I was going it probably would be train to Nuremberg and bus to Prague via bahn.
As I would rather take a beating than deal with airport hassle - I would most definitely take a train. Plus you would get to see a lot of country. It is anywhere from a 6 to 8 hr trip (6 hours if you take the express bus for a portion) 7 1/2 to 8 if you stay on the train.