Food intake and eating patterns, body functions and composition are significantly altered by short-duration space flight. Prolonged missions lasting weeks or months further aggravate these changes, and are responsible for acute or chronic physical impairments at return to ground conditions. Current projects of missions to Mars, resulting in 2 years of microgravity conditions, stress the critical need for the development of optimal nutritional programs and physical countermeasures to prevent body mass and function alterations. This review outlines ground models of microgravity simulation, summarizes the major effects of weightlessness on body composition, protein metabolism, hormonal pattern, and muscle function, and addresses contradictory findings related to the oxidative stress secondary to space flight. Potential countermeasures, such as nutrient intake and physical conditioning, as well as areas of interest for future research both in ground and space medicine, are discussed.