The human selenoproteome is composed of approximately 25 selenoproteins, which cotranslationally incorporate selenocysteine, the 21st amino acid. Selenoprotein expression requires an unusual translation mechanism, as selenocysteine is encoded by the UGA stop codon. SECIS-binding protein 2 (SBP2) is an essential component of the selenocysteine insertion machinery. SBP2 is also the only factor known to differentiate among selenoprotein mRNAs, thereby modulating the relative expression of the individual selenoproteins. Here, we show that expression of SBP2 protein varies widely across tissues and cell types examined, despite previous observations of only modest variation in SBP2 mRNA levels. This discrepancy between SBP2 mRNA and protein levels implies translational regulation, which is often mediated via untranslated regions (UTRs) in regulated transcripts. We have identified multiple sequences in the SBP2 3' UTR that are highly conserved. The proximal short conserved region is GU rich and was subsequently shown to be a binding site for CUG-BP1. The distal half of the 3' UTR is largely conserved, and multiple proteins interact with this region. One of these proteins was identified as HuR. Both CUG-BP1 and HuR are members of the Turnover and Translation Regulatory RNA-Binding Protein family (TTR-RBP). Members of this protein family are linked by the common ability to rapidly effect gene expression through alterations in the stability and translatability of target mRNAs. The identification of CUG-BP1 and HuR as factors that bind to the SBP2 3' UTR suggests that TTR-RBPs play a role in the regulation of SBP2, which then dictates the expression of the selenoproteome.