The effect of microgravity has been extensively studied on human lymphocytes in several space missions. A clear distinction must be made between two kinds of experiments: (i) with cells purified from the peripheral blood of test subjects before flight and then exposed inflight to mitogens and other activators (these are called in vitro experiments), and (ii) with lymphocytes from crewmembers of space missions exposed to mitogens prior to and after flight (ex vivo experiments). The first approach can be considered as basic research in cell biology in space; the second contributes to identifying the effects of the stress of spaceflight on the immune response of astronauts. The results from in vitro experiments have clearly shown that lymphocyte activation is nearly totally depressed in microgravity. This activation depression is confirmed by investigations on Earth in the fast rotating clinostat. Conversely, activation is increased when lymphocytes are cultured at 10 g in a centrifuge. In microgravity cell adhesion may be reduced, thus partly accounting for the decreased cell activation. The results of the experiments conducted at 10 g are due to a simultaneous activation of T- and B-lymphocytes by concanavalin A. The reduced activation observed in lymphocytes from crewmembers of space missions can be ascribed to both the physical and psychological stress of spaceflight. This observation was confirmed by investigations on subjects undergoing stress on Earth.