The description of the ERα-deficient male in 1994 provided the initial evidence that estrogen may play an important role at least in bone mass acquisition and epiphyseal fusion not only in girls, but also in boys. Since then, several direct interventional studies in adult and aging men with selective replacement of testosterone or estrogen have now provided compelling evidence that in men, estrogen is the dominant sex steroid regulating bone metabolism. Recent evidence also demonstrates that estrogen regulates fat accumulation and somewhat surprisingly, libido, in men. In population studies, serum estrogen levels are generally associated with fracture risk in men to a much greater extent than serum testosterone levels. The clinical investigative studies with selective testosterone or estrogen replacement have also uncovered early effects of sex steroid withdrawal on the “uncoupling” and subsequent “recoupling” of bone resorption and bone formation. This led our group, along with others, to identify several “clastokines”, or osteoclast-derived secreted factors that regulate bone formation, including sphingosine 1-phosphate, BMP6, and Wnt10b. These findings also have significant clinical implications, including 1) the use of serum estradiol levels in the evaluation of male osteoporosis; 2) the use of selective estrogen receptor modulators in male osteoporosis; 3) a cautionary note regarding the possible efficacy of non-aromatizable selective androgen receptor modulators in preventing bone loss in men; and 4) based on the osteoclast-derived osteoblast coupling factors, the potential development of novel bone formation-stimulating agents.