Osteoporosis is a common skeletal disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Bone mineral density (BMD) is considered the best established risk factor for osteoporotic fractures.Over the last years a large number of studies have pointed to the variability in many target genes and their relation with BMD and other determinants of fracture risk such as ultrasound bone properties, skeletal geometry and bone turnover markers. The importance of genetic factors in the bone quality is substantial, but no consensus exists yet on the genes that are involved.Although osteoporosis is world healthy problem, there are many differences in human ethnics regarding both disease morbidity and drug treatment efficacy. Heterogeneity in drug response may reflect varying responsiveness to osteoporosis treatments due to allele variation in signaling pathway genes such as vitamin D receptor (VDR) or estrogen receptor α (ERα). Polymorphisms of VDR and ERαloci appear genetic determinants of their corresponding hormonal treatment response such as vitamin D and estrogens. Because of their specific ethnic distribution, polymorphisms of VDR and ERαgenes may be involved in reported human differences of osteoporosis treatment responses.Knowledge of the molecular and functional consequences of the gene polymorphisms is crucial to fully appreciate their significance and understand their potential clinical implications. Future studies and preventive strategies to management osteoporosis need to take in account these genetic factors.