While estrogen was known to be the major hormonal regulator of bone metabolism in women, somewhat unexpected were a series of clinical-investigative findings from our group and others demonstrating that estrogen also has a dominant effect in mediating both the acquisition and loss of bone in men. Moreover, in contrast to pre- versus post-menopausal women who are either estrogen sufficient or deficient, respectively, biologically available estrogen levels in men span an intermediate range, allowing for the definition of in vivo dose responses of estrogen on bone, which are relevant to our understanding of bone loss in both sexes.