Mechanical strain-related stimuli engendered during osteogenic load bearing of the young, healthy skeleton locally trigger functionally appropriate bone formation by osteoblast cells. The processes underlying this response become deficient with advanced age and impaired estrogen signaling. Age-related and postmenopausal bone loss and architectural deterioration in humans underlie fragility fractures characteristic of osteoporosis. This chapter explores the bases and potential application of estrogen-targeting therapies in enhanceing skeletal responses to mechanical loading. In vitro cellular signaling responses to mechanical strain facilitated by estrogen receptors (ERα and ERβ) are introduced and extrapolated to in vivo findings in mice with transgenic perturbations of the estrogen receptors or withdrawal of circulating estrogens. Human genetic studies and exercise intervention trials in individuals with estrogen receptor polymorphisms are also presented. Taken together, these studies suggest that estrogen receptors, acting locally in osteoblast-lineage cells, facilitate bone gain in response to mechanical strain by enhancing mechanoresponsive signaling pathways in these cells.