Extreme environment is an inhabitable ambience affecting the normal physiology of the human body. Radiation personnel who travel to low earth orbit for long space journey may face a detrimental effect of the influx of radiation source during extravehicular activities that lead to chronic endothelial injury of the underlying cells. In addition, the low pressure oxygen (hypobaria) of the space station environment could potentially underpin cellular changes in sensitive organ, i.e., the brain cells. These factors could pose a threat to the reconditioning of the vital functioning organs. Spatial oxygen concentration will decrease to >20% to a higher altitude of 5300 m, whereas insulin and C-peptide concentrations are increased by 200% during the endurance stay at the altitude for 2 weeks. Therefore, the potential increase in fasting insulin, homeostatic model assessment of insulin resistance, and glucagon influences the elevation of markers of oxidative stress and the inflammatory markers. The use of advance molecular imaging biomarkers that range from the inflammatory markers, hybrid imaging markers, such as functional magnetic resonance imaging, and genetic markers could discover the early changes of the cellular reprogramming in cells that could avert the ongoing process of oxidative stress injury via mitigation programs and preventive measures. In this review, specific documentation on the various ambiences of the physiological environment, i.e., hypobaria, chronic ionizing radiation, and hypergravity pull, would be discussed with the potential molecular imaging markers used to exploit the early physiological, inflammatory, and genetic deconditioning that underpin the cellular changes leading to the untoward effect on oxidative stress.