Structure and microarchitecture are determinant aspects of bone strength and essential elements for the assessment of bone mechanical properties. The main structural determinants of bone mechanical strength include width and porosity in the cortical bone; shape, width, connectivity, and anisotropy in the trabecular bone. There are several methods to assess bone architecture, particularly at the trabecular level. Two different approaches can be identified. The first is based on the use of optical microscopy and on the principles of quantitative histology, which evaluate microarchitecture two-dimensionally. The second applies the most modern diagnostic techniques, employing computed tomography and magnetic resonance to obtain and analyze three-dimensional images. From a clinical point of view, microarchitecture is an interesting aspect to study and define specific patterns, such as glucocorticoid-induced osteoporosis, or to evaluate bone alterations in transplanted patients. Microarchitecture seems to be a determinant of bone fragility independent of bone density. Moreover, bone microarchitecture seems to be important to understand the mechanisms of bone fragility as well as the action of the drugs used to prevent osteoporotic fractures. Several in vivo studies (on animals and humans) showed important findings on the effects of different treatments on microarchitecture. Bisphosphonates and parathyroid hormone seemed to preserve or even improve microarchitecture. These observations can provide an additional interpretation for the anti-fracture effect of drugs from a structural viewpoint. The challenge for the future will be to evaluate bone quality in vivo with the same or better resolution and accuracy than the invasive methods in use today.