What struck me at the end of the Mars500 mission was just how happy/together the crew looked. It's an incredible experiment for sure, locking 6 people (all male?...is this realistic?) into something which looked like a Swedish Sauna for 520 days, simulating docking, landing, orbits etc...but the three critical human (never mind the technical) factors which make it real still need to be tested
They being
1: The psychological effects of knowing that you're millions of miles away with absolutely no chance of a rescue should something go wrong. Mars500 crew knew they were in a hangar, and could step out at any minute...so that element still needs to be tested...how? It's a good question, but probably the only way is to just do it, much like the Apollo program just "did it" to test systems. The effects of being removed from your family I think are also compounded by real distance.
2: Weightlessness and the effects on the body for 520 days - We've come close with ISS and MIR over the years, but this is still a step above that, and again, you're compounding the medical effects with a lack of a suitable radiation shield which the Earth provides.
3. The post mission effect. Trivial compared to the other two, but someone will be the first/second etc person to set foot on Mars. Look what that did to Neil Armstrong and Buzz Aldrin. Being able to manage that in the 60s without the massively increased media (good and bad) was tough enough...doing it in the digital age...ratchet that up a notch or six..
Congratulations though to a team who've proved many of the elements for long duration missions can be achieved, it's a small step for man, and a giant leap towards Mars
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