The mass and architecture of the skeletal system adapt, to some extent, to their mechanical environment. A site-specific bone loss of 1-2% is observed in astronauts and in-flight animals after 1 month of spaceflight. Biochemical data of astronauts and histomorphometric analysis of rat bones show that the change in bone mass is a result of decreased bone formation in association with normal (or increased) bone resorption. The changes in bone formation appear to be due in part to decreased osteoblast differentiation, matrix maturation, and mineralization. Recent data show that spaceflight alters the mRNA level for several bone-specific proteins in rat bone, suggesting that the characteristics of osteoblasts are altered during spaceflight. A possible underlying mechanism is that osteoblasts themselves are sensitive to altered gravity levels as suggested by several studies investigating the effect of microgravity on osteoblasts in vitro. Changes in cell and nuclear morphology were observed as well as alterations in the expression of growth factors (interleukin-6 and insulin-like growth factor binding proteins) and matrix proteins (collagen type I and osteocalcin). Taken together, this altered cellular function in combination with differences in local or systemic factors may mediate the effects of spaceflight on bone physiology.