The ancient greeks wondered about geometric problems like whether it was possible to draw a square with the same area as a given circle, or whether it was possible to trisect an angle. Humanity didn't prove those to be impossible until the 1800s - it took over 2000 years to go from hypothesis to proof! Enormously important new fields of math were invented to solve these seemingly straightforward problems.
The most difficult unsolved math problem that we have right now is whichever one will take 2000 years to solve. We might never actually see something like that again, since the field of mathematics has matured so much, but there are still plenty of examples of questions that are 100+ years old that we still can't answer.