After the realization of the International Space Station, human exploratory missions to Moon or Mars, i.e. beyond low Earth orbit, are widely considered as the next logical step of peaceful cooperation in space on a global scale. Besides the human desire to extend the window of habitability, human exploratory missions are driven by several aspects of science, technology, culture and economy. Mars is currently considered as a major target in the search for life beyond the Earth. Understanding the history of water on Mars appears to be one of the clues to the puzzle on the probability of life on Mars. On Earth microorganisms have flourished for more than 3.5 Ga and have developed strategies to cope with so-called extreme conditions (e.g., hot vents, permafrost, subsurface regions, rocks or salt crystals). Therefore, in search for life on Mars, microorganisms are the most likely candidates for a putative biota on Mars and the search for morphological or chemical signatures of life or its relics is one of the primary and most exciting goals of Mars exploration. The presence of humans on the surface of Mars will substantially increase this research potential, e.g., by supporting deep subsurface drilling and by allowing intellectual collection and sophisticated in situ analysis of samples of astrobiological interest. On the other hand, such long-duration missions beyond LEO will add a new dimension to human space flight, concerning the distance of travel, the radiation environment, the gravity levels, the duration of the mission, and the level of confinement and isolation the crew will be exposed to. This will raise the significance of several health issues, above all radiation protection, gravity related effects as well as psychological issues. Furthermore, the import of internal and external microorganisms inevitably accompanying any human mission to Mars, or brought purposely to Mars as part of a bioregenerative life support system needs careful consideration with regard to planetary protection issues. Therefore, before planning any human exploratory mission, the critical issues concerning human health and wellbeing as well as protection of Mars in its pristine condition need to be investigated.