Osteoporosis is a common disease associated with reduced bone mineral density, affecting up to 40% of women and 12% of men at some point during life. Although osteoporosis is multifactorial, genetic factors play an important role in the pathogenesis of osteoporosis, as up to 75% of the variance in bone mass-a major risk factor for osteoporotic fracture-is genetically determined. Segregation analysis of bone mass in families has suggested a model whereby bone mass is under the control of a large number of genes with small effect, rather than a few genes with large effect. Although the molecular-genetic basis by which bone mass is regulated is incompletely defined, polymorphisms of several candidate genes have been linked to bone mass in clinical studies. Polymorphisms in the gene encoding the vitamin D receptor have been extensively investigated with differing results, and interleukin-6, transforming growth factor beta, and the estrogen receptor have been associated with bone mass in isolated studies. Recent work has identified a polymorphism in the binding site for the transcription factor Sp1 in the collagen type I alpha 1 gene. This polymorphism is associated with bone mass and osteoporotic fracture in three distinct populations, suggesting that the polymorphism may act as a marker for low bone density and fracture risk. Further studies will uncover many new genes and candidate loci that relate to bone mass. This information may be of value in defining new therapeutic targets in the prevention and management of osteoporosis and in developing genetic tests to assess osteoporotic fracture risk.