Several hormonal and metabolic factors have been found to influence the production of sex hormone-binding globulin (SHBG). In addition, twin studies have suggested that genetic factors may also contribute to variation in SHBG levels. Given the clinical significance of SHBG in regulating bioavailable sex steroid hormones, a number of studies examined the potential association between polymorphisms of SHBG gene and serum SHBG levels as well as their possible contribution in the pathogenesis of common diseases. Thus, polymorphisms of SHBG, altering either the production or the metabolism of the protein, may represent part of the genetic background of sex steroid hormone activity in humans. There is considerable heterogeneity in the results of these studies indicating the multiplicity of the factors influencing SHBG variation. However, the weight of evidence suggests that some common genetic variants of SHBG may influence SHBG levels and in part contribute to the phenotypic expression of human diseases.