This review summarizes the evidence to support the possible benefit of the combination of vitamin D and soy phytoestrogens on post-menopausal bone loss. Clinical evidence for maximal vitamin D-mediated Ca absorption does not completely explain the optimal vitamin D status for maximal BMD or BMC and lacks correlation of vitamin D-related Ca absorption and BMD or BMC in post-menopausal women. The benefit of vitamin D on bone seems to be stronger through the direct effect on osteoblasts and osteoclasts. Soy phytoestrogens in combination with vitamin D may synergistically induce osteoblast activation and prevent pre-osteoclast and osteoclast differentiation, through the increase of vitamin D metabolites, VDR, and ER actions. More research is required to identify the causal factors and the mechanism of the benefits of vitamin D and phytoestrogens on bone in post-menopausal women.