We have previously shown that fluid balances and body fluid regulation in microgravity (microG) differ from those on Earth (Drummer et al, Eur J Physiol 441:R66-R72, 2000). Arriving in microG leads to a redistribution of body fluid-composed of a shift of fluid to the upper part of the body and an exaggerated extravasation very early in-flight. The mechanisms for the increased vascular permeability are not known. Evaporation, oral hydration, and urinary fluid excretion, the major components of water balance, are generally diminished during space flight compared with conditions on Earth. Nevertheless, cumulative water balance and total body water content are stable during flight if hydration, nutritional energy supply, and protection of muscle mass are at an acceptable level. Recent water balance data disclose that the phenomenon of an absolute water loss during space flight, which has often been reported in the past, is not a consequence of the variable microG. The handling of sodium, however, is considerably affected by microG. Sodium-retaining endocrine systems, such as renin-aldosterone and catecholamines, are much more activated during microG than on Earth. Despite a comparable oral sodium supply, urinary sodium excretion is diminished and a considerable amount of sodium is retained-without accumulating in the intravascular space. An enormous storage capacity for sodium in the extravascular space and a mechanism that allows the dissociation between water and sodium handling likely contribute to the fluid balance adaptation in weightlessness.