There are two classes of problems; physical and psychological.
Doctors report that prolonged exposure to low gravity causes bone mass to be lost, and major changes in the cardiovascular system. After 100 days, we know that Russian cosmonauts from the MIR space station return to Earth in pretty bad condition close to the threshold where irreversible changes may be occurring. This is the major problem we know about in space travel. The body does not respond well to low gravity, and studies on the Space Station in the next decade will tell us more about this, and if there are any ways to avoid damage.
After 200 - 300 days enroute to Mars, and 200 - 300 days to return, the astronauts bones and heart would not be able to return to Earth without fatal damage to the astronaut. And then there is the problem with cosmic rays, and the high energy particles produced by solar storms. These would be lethal to astronauts caught in interplanetary space. This means we have to have ways of predicting when they will happen during a round trip journey lasting hundreds of days. No such ability is currently available.
Imagine spending 260 days cooped up in a single room in your house, with 2 or three other people. Imagine the odors, the color of the walls and ceiling, the static look of the furnishings, the increasingly bad and delayed TV reception from Earth, and the limited reading material, and the monotonous daily routines. This is a psychologically volatile situation for humans accustomed over millions of years to highly varied surroundings. Astronauts orbiting the Earth for months at a time, knowing that they can abort the experiment at any time they want and come back to Earth, still experience many different psychological states. Imagine knowing that you can't abort the mission until you reach, say, Mars and even then your surroundings look nothing like Earth, but that you have to wait another 300 days to see the blue skies and green grass of Earth, and other humans.
Because of these factors, I can not imagine us going to Mars for 50 years. There are, however, no similar problems with creating enormous colonies on the Moon.