From Garrett Reisman:

The biggest challenge is dealing with the radiation. We've gotten pretty good at spending up to a year in space on the ISS, but we fly under the Earth's magnetosphere and are still mostly protected from the nasty radiation outside of low earth orbit - solar particle events (SPEs) and Galactic Cosmic Radiation (GCRs). When we go back to the Moon or on to Mars we will not have that protection. A 2.5 year round-trip journey to Mars would result in a radiation dose equivalent of 1 Sievert which is 10 times as much as you would take on the ISS for 6 months and would be at about the NASA career limit for most astronauts.

The thing is, we know very well what kind of radiation is up there - how much flux density and particle energies to expect, but we have little knowledge of exactly what that type of radiation does to human tissue. So we are still learning, and there is a lot of uncertainty about how dangerous this will be for our Mars colonists.