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Over the past half century, our understanding of the physiological effects of space exploration and microgravity exposure have improved immensely. Microgravity causes incredible changes to the human body that increase risk of injury upon return to Earth and lunar/planetary egress scenarios. This is due to deconditioning of the cardiovascular and skeletal muscle systems that reduce aerobic capacity and muscular strength. With upcoming exploration class missions, such as NASA’s Artemis lunar exploration program which aims to send the first female astronaut to the lunar surface by 2030, as well as a long-term goal of Martian exploration, maintaining astronaut health during extended-duration space flight is critical for achieving mission objectives. However, our understanding of these physiological implications due to microgravity are based primarily on flight studies of male astronauts and 1g bedrest analog study participants, with few investigations focusing specifically on females. Innate physiologic differences in endocrine signaling and reproductive function impact sex-dependent responses to various health conditions, treatments, and environmental factors in nearly every system in the body. Therefore, to assume comparable alterations in females in response to microgravity exposure may be inappropriate and consequentially, could lead to lasting impacts on female astronaut health and impact mission success. Moreover, differences in sex hormones may also influence the regulation of cardiovascular control during egress activity after space flight-induced deconditioning and blood volume loss (i.e., risk for orthostatic intolerance). Other potential physiological systems and factors related to musculoskeletal health and aerobic capacity that warrant investigation with respect to microgravity include endocrine/reproductive function, vascular control, bone mineral density/microarchitecture, and soft-tissue health. The purpose of this investigation is two-fold: 1) to summarize the data available from space flight and simulated bedrest analog exposures to begin addressing these gaps in knowledge regarding impacts to female astronaut health, and 2) to describe differences in demographic health characteristics, injury prevalence, and aerobic capacity and muscular strength in NASA female and male astronauts. Female astronauts make up 50% of Artemis-specific astronaut corps and the extent to which microgravity exposure impacts female cardiovascular and musculoskeletal health, and whether these alterations are consistent with their male counterparts, is inconclusive. With the growing inclusion of female astronauts in the NASA space program and the increased duration of missions beyond low Earth orbit, a greater understanding of the sex-specific adaptation to space travel will help determine the development of appropriate countermeasures for minimizing risk and maintaining health of all astronauts.