Selenium (Se), in the form of the 21st amino acid selenocysteine, is an integral part of selenoproteins and essential for mammals. While a large number of health claims for Se has been proposed in a diverse set of diseases, little is known about the precise molecular mechanisms and the physiological roles of selenoproteins. With the recent and rigorous application of reverse genetics in the mouse, great strides have been made to address this on a more molecular level. In this review, we focus on results obtained from the application of mouse molecular genetics in mouse physiology and discuss these insights into the physiological actions of selenoproteins in light of evidence from human genetics.