Space is one of the most extreme environments imaginable. Beyond the insulating atmosphere of the Earth, astronauts are subjected to extremes of zero grvaity, isolation and confinement and a significantly increased threat of radiation damage which pose challenges and changes on their bodies, in addition, all these factors have a direct impact on the feasibility and success of such long-duration exploration missions with a human crew. So if we want to send a human crew to the Moon, to Mars or in general into Deep Space, we need to ensure that astronauts remain fit, functional and healthy throughout the entire mission, from the very beginning to the bitter end, we need to ensure that our crew gets to their destination in deep space and then of course back, safely – ESA’s Human Research Programme contributes to that endeavour through all its different research projects. The talk will provide an overview of all activities on the very diverse research platforms that are part of ESA’s Human Research Programme, the results of which will provide more insight into these challenges and changes over a longer period of time, and present a stepping stone for even longer missions such that when we send humans on a journey to Mars, we will make sure that we have conquered the unknowns of the most extreme environment of all to ensure a safe trip home back to the envinroment we know and love.