Although differences exist, hypobaric and hyperbaric exposures share common physiological, biochemical and clinical features and their comparison may provide further insight into the mechanisms of decompression stress. Although altitude decompression illness (DCI) has been experienced by high-altitude Air Force pilots and is common in ground-based experiments simulating decompression profiles of extravehicular activities (EVA's) or astronauts' space walks, no case has been reported during actual EVA's in the non weight-bearing microgravity environment of orbital Space Missions. We are uncertain whether gravity influences decompression outcomes via nitrogen tissue wash-out or via alterations related to skeletal muscle activity. However, robust experimental evidence demonstrated the role of skeletal muscle exercise, activities and/or movement in bubble formation and DCI occurrence. Dualism of effects of exercise, positive or negative, on bubble formation and DCI is a striking feature in hypobaric exposure. Therefore, the discussion and the structure of this review are centered on those highlighted unresolved topics about the relationship between muscle activity, decompression and microgravity. This article also provides, in the context of altitude decompression, an overview of the role of denitrogenation, metabolic gases, gas micronuclei, stabilization of bubbles, biochemical pathways activated by bubbles, nitric oxide, oxygen, anthropometric or physiological variables, Doppler-detectable bubbles and potential arterialization of bubbles. These findings and uncertainties will produce further physiological challenges to solve in order to line up for the programmed human return to the Moon, the preparation for human exploration of Mars and the EVA's implementation in a non-zero gravity environment.