Osteoporosis is partly genetically determined. The genetics of osteoporosis is polygenic in nature with multiple common polymorphic alleles interacting with each other and environmental factors to determine bone mass. A number of studies have attempted to dissect the genetic factors responsible for the pathogenesis of osteoporosis using genome-wide scanning and the candidate gene approach. However, the results of such studies among different populations have been mostly inconsistent, suggesting genetic heterogeneity of osteoporosis. It is likely that the cohort of genes indicating predisposition to the risk of osteoporosis may be different among populations with different ethnic backgrounds. The successful identification of susceptibility genes for osteoporosis should prove to be helpful in targeting preventive and therapeutic measures to individuals at higher risk and to render the effort more cost-effective. Information with regard to genetic variations is also likely to be useful in targeting preventive or therapeutic measures to subjects genetically determined to have better responsiveness. Intestinal calcium absorption is dependent on vitamin D receptor gene polymorphisms. Skeletal responsiveness to estrogen, particularly at lower doses, is related to polymorphisms in the estrogen receptor-alpha gene. Recently, circulating homocysteine levels have been shown to be associated with fracture risk. Folate and vitamin B supplements for reducing serum homocysteine and fractures in postmenopausal women have not been fully investigated. However, there is an interaction between folate status and methylenetetrahydrofolate reductase gene polymorphism on bone phenotypes. Due to recent technological advances, whole-genome association study is becoming more feasible. Genomic information with regard to the susceptibility to osteoporosis and the responsiveness to preventive or therapeutic modalities should supplement rather than replace conventional clinical information. Clinical decision should also take into account the social, health and economic perspectives in order to balance the benefit of novel clinical strategies against the associated risks and available resources.