The study of metabolic adaptations to microgravity is relatively recent in bioastronautics. The cumbersome nature of the clinical tests to be carried out to study endocrinologic and metabolic adaptations to the space environment has been and still is an obstacle to experimental studies. Almost all the results at our disposal have been obtained through simulations of weightlessness using ground-based space analogs including head-down tilt bed rest (HDBR) at 6 degrees, dry immersion models in humans, and hind-limb suspension in rodents. These studies demonstrate the development of hormonal and metabolic disorders across multiple levels, from the whole body to tissues, cells, proteins, and genes. Intermediary metabolism is at the crossroads of all physiological systems. Thus, changes induced by microgravity can contribute to alterations in other physiological systems. These alterations may manifest as cardiovascular deconditioning, reduced muscular endurance and performance, and muscle atrophy. Furthermore, when examining the impact on the skeletal system, disturbances in intermediary metabolism are not only associated with the well-documented decrease in bone density and increased fragility among astronauts but can also affect another critical bone function—hematopoiesis. This, in turn, influences the immune response and the body’s ability to heal, highlighting the far-reaching consequences of metabolic changes in space (Fig. 1). This chapter reviews how metabolism adapts to both short-term and long-term exposure to microgravity, indicating a series of metabolic events triggered by this condition. With forthcoming missions to the Moon and Mars, it is essential to understand these microgravity-induced metabolic changes to assess and enhance countermeasure programs. The chapter also summarizes the metabolic impacts of exercise and nutrition countermeasures tested so far and outlines future directions and major challenges for anticipated human interplanetary exploration.