The high-affinity binding of the sex hormone-binding globulin (SHBG) for testosterone and to a lesser extent for estradiol influences the circulating levels of these sex steroid hormones, their biodisposal to target cells as well as their mutual balance. Although the regulation of SHBG is still not completely understood, in vitro studies performed with human hepatocarcinoma (Hep G2) cells have shown that estrogens and thyroxine stimulate SHBG secretion, by increasing the steady state of its mRNA concentrations. These observations are in good agreement with studies showing that SHBG levels increase during oral administration of estrogens as well as in patients with thyrotoxicosis. Interestingly, SHBG levels are normal in syndromes such as the abnormal transport of thyroid hormones and/or the syndrome of thyroid hormone resistance, which can be confused with thyrotoxicosis. By contrast, the effects of androgens are controversial. In many patients with hirsutism, SHBG concentrations are low and correlate negatively with both body mass index and fasting insulin levels. Because of the inhibitory effect of both insulin and insulin-like growth factor-1 on SHBG secretion by Hep G2 cells in vitro, it has been proposed that SHBG levels could be a marker of insulin resistance and/or hyperinsulinism in humans. Furthermore, an increased risk for either noninsulin-dependent diabetes and/or the overall mortality are associated with decreased SHBG levels in postmenopausal women. Finally, in men, SHBG levels are positively correlated with the concentration of high-density lipoprotein cholesterol. Therefore, the measurement of SHBG in clinical practice can be a useful diagnostic tool for: (1) correctly interpretating testosterone and estradiol serum concentrations; (2) investigating androgen-estrogen balance in gonadal and sexual dysfunctions; (3) assessing the peripheral effect of the hormones which regulate SHBG productions, and (4) evaluating insulin resistance and cardiovascular risk.