Of all the code words in the genetic code, UGA serves more functions than any other codon. In mammals, it dictates insertion of selenocysteine (Sec) into the growing polypeptide chain and termination of protein synthesis. It may also be suppressed by a variety of aminoacyl-tRNAs and be involved in translational reading gaps, thus extending protein synthesis beyond the UGA termination signal. Each of these roles of UGA in mammalian protein synthesis is discussed.