Selenium deficiency in humans or livestock and impaired selenoprotein synthesis in patients due to mutations in relevant genes have revealed the importance of selenoproteins for healthy life. Twenty-four genes for selenoproteins are encoded in the murine genome, and most of them have been genetically inactivated. We summarize the results from those studies that have provided a series of intriguing mechanistic details about the importance of selenoprotein-dependent processes for proper neuronal, retinal, cardiac, endothelial, and renal function as well as the contribution of selenoprotein activity to the endocrine, immune and gastrointestinal systems, and reproduction. Mouse models were particularly useful for the study of organs that are not easily accessible for biopsy in humans. While four selenoproteins have proven to be crucial for murine embryo and tissue development, others confer more specific functions particularly in response to stress.