Selenium is an essential trace element that is incorporated into proteins as selenocysteine (Sec), the twenty-first amino acid. Sec is encoded by a UGA codon in the selenoprotein mRNA. The decoding of UGA as Sec requires the reprogramming of translation because UGA is normally read as a stop codon. The translation of selenoprotein mRNAs requires cis-acting sequences in the mRNA and novel trans-acting factors dedicated to Sec incorporation. Selenoprotein synthesis in vivo is highly selenium-dependent, and there is a hierarchy of selenoprotein expression in mammals when selenium is limiting. This review describes emerging themes from studies on the mechanism, kinetics, and efficiency of Sec insertion in prokaryotes. Recent developments that provide mechanistic insight into how the eukaryotic ribosome distinguishes between UGA/Sec and UGA/stop codons are discussed. The efficiency and regulation of mammalian selenoprotein synthesis are considered in the context of current models for Sec insertion.