The elephant in the room ... for manned space travel outside the Earth system (such as a trip to Mars) is the effects of cosmic rays on humans: basically the same as any other high doses of energetic ionizing radiation. Think cancer and ugly deaths.
The van Allen belts around the Earth protect our astronauts in Earth orbit, and the trip to the moon is so short that total exposures are small enough to not be life-threatening. None of this is true on long and distant voyages, and nobody knows how to fix that. This is a good backgrounder on the topic, which seems to be studiously ignored in all of NASA's breathless pressers.
Personally, I think all manned space exploration should be stopped until and if a solution for this problem is found. The presence of this problem is enough of a reason all by itself to have NASA (and any other government-funded space program) to focus exclusively on robotic exploration.
Not that either common sense or my opinion counts for anything, of course. I'm just whistling in the wind here...
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