One of the most pressing concerns, researchers say, would be the effect on their vision, as acceleration on launch followed by long exposure to weightlessness has been shown to change the shape of astronaut eyeballs, swell the optic nerves and cause blurred vision -- problems that have been found to persist long after return to Earth and normal gravity.
"When you're talking about missions that might be two years round trip, it has to be in the back of your mind that this could be a potential limiting factor," Larry A. Kramer, a professor of diagnostic imaging and intervention at the University of Texas, recently told The New York Times.
A NASA survey of about 300 astronauts, 30 percent who have flown on two-week space shuttle missions and 60 percent who've spent six months aboard the International Space Station, indicated they had a gradual blurring of eyesight.
"We are certainly treating this with a great deal of respect," said Dr. Rich Williams, NASA's chief health and medical officer. "This [eye condition] is comparable to the other risks like bone demineralization [loss] and radiation that we have to consider. It does have the potential for causing mission impact."
Cosmic radiation exposure is another concern for long-voyage astronauts, who would be without the protection the Earth's atmosphere provides.
Astronauts on a mission to Mars could face severe radiation threats from solar flares that send charged particles and high radiation levels streaming into space.
Although rare, such events could be deadly to inhabitants of a spacecraft, because without heavy shielding they could sustain acute radiation poisoning.
Bone loss is another effect of zero gravity that has been found to be progressive and continuous throughout long periods spent in weightless conditions.
Astronauts in a weightless environment lose calcium from all their bones but primarily from the weight-bearing bones like the hips, spine, ankles and upper femur.
The bone loss is about 1 percent per month for the duration of time spent in zero gravity.
The effect was first noticed in crews of the Skylab missions of the 1970s and the Russian Space Station Mir.
On return to Earth, calcium and bone level are slow to return to normal.
The members of one Mir mission crew needed three months back on Earth for their levels to return to normal.
A final hurdle for a mission to Mars isn't physical, but rather psychological, as a small number of people would have to cooperate in a cramped, isolated and risk-laden environment for a year or more -- a situation that could produce stress, tension and perhaps even severe psychiatric problems, NASA's 2009 Human Research Program report said.
The report, based on studies in Antarctica and isolated environments underwater, found a risk of "increased human performance errors due to sleep loss, fatigue, work overload, and circadian desynchronization; and, increased errors due to poor team cohesion and performance, inadequate selection/team composition, inadequate training and poor psychosocial adaptation."
So while the technical challenges of a multi-year mission within our solar system are undeniably daunting, the human element -- their safety, physical and psychiatric well-being, and even their successful return -- may prove to be an even bigger concern.