To expand the human exploration footprint and reach Mars in the 2030s, we must explore how humans survive and thrive in demanding, unusual, and novel ecologies (i.e., extreme environments). In the extreme conditions encountered during human spaceflight, there is a need to understand human functioning and response in a more rigorous theoretically informed way. Current models of human performance in space-relevant environments and human space science are often operationally focused, with emphasis on acute physiological or behavioral outcomes. However, integrating current perspectives in human biology allows for a more holistic and complete understanding of how humans function over a range of time in an extreme environment. Here, we show how the use of evolution-informed frameworks (i.e., models of life history theory to organize the adaptive pressures of spaceflight and biocultural perspectives) coupled with the use of mixed-methodological toolkits can shape models that better encompass the scope of biobehavioral human adjustment to long-duration space travel and extra-terrestrial habitation. Further, we discuss how we can marry human biology perspectives with the rigorous programmatic structures developed for spaceflight to model other unknown and nascent extremes.