The essential trace element selenium (Se) is a central constituent of 50-70 selenoprotein variants encoded by 25 human genes. Incorporation of the 21st proteinogenic amino acid selenocysteine occurs cotranslationally and requires peculiar features of the corresponding mRNA, a dedicated tRNA and a complex translational machinery for decoding UGA in this context. Thyroid hormone (TH) synthesis and protection of the thyroid gland from H2O2 and reactive oxygen species derived therefrom as well as TH activation and inactivation by deiodinase enzymes requires Se. Altered Se status has been associated with benign (goiter and autoimmune thyroid disease) and malignant thyroid maladies and several but not all Se supplementation studies reported on beneficial effects. Whether adequate or therapeutic Se supply is advantageous for the functional unit of the thyroid, the angiofollicular unit, or for the immune system or for both requires more controlled clinical trials and further in vitro and animal experimental studies. Development of proper diagnostic tests to monitor Se status of the thyroid gland and identification and validation of clinically useful thyroid-related biomarkers for Se action on the largest human endocrine gland are required. Several knockout and transgenic mouse models have revealed valuable insight into the role of Se and selenoprotein function for the thyroid. Recently, first human mutations in genes encoding a selenoprotein and a component involved in selenoprotein biosynthesis have been identified, the latter with marked impairment of TH homeostasis.