3′ UTR functions as the availability of experimental approaches is often crucial for progress and discoveries. Compared with research on transcription or translation regulation, or on microRNA (miRNA)-mediated posttranscriptional regulation, research on miRNA-independent functions of 3′ UTRs lags far behind. Most functions of 3′ UTRs are mediated by RNA-binding proteins (RBPs). But, in contrast to miRNA target sites, the binding motifs for many RBPs are still not known (Baltz et al. 2012; Ray et al. 2013; Dominguez et al. 2018). And even if they are known, clear functional effects often require the motifs to be present several times. As the motifs are often spread out over large distances, functional motifs can often not be identified using deletion mutants (Besse et al. 2009; Kristjansdottir et al. 2015; Ma and Mayr 2018). Moreover, many RBPs bind to the same motif (Ray et al. 2013; Dominguez et al. 2018), and it is usually unknown whether they compete or cooperate (Hennig and Sattler 2015). Finally, more than half of human genes use alternative cleavage and polyadenylation to generate mRNA isoforms that differ only in their 3′ UTRs (Lianoglou et al. 2013). This makes research on 3′ UTR isoform–specific functions challenging as the amino acid sequences of the proteins generated from the alternative 3′ UTR isoforms are identical.

This review summarizes how research on 3′ UTR functions has been approached in the last 25 years, what has been learned, and how it could be addressed in the future. Several topics relevant for 3′ UTR biology are being reviewed elsewhere in this collection, including regulation by miRNAs, RNA editing, RNA structure, the identification of RBPs, and RNA–protein interactions. Also, several “noncanonical” functions of 3′ UTRs were reviewed recently and are not included here (Mayr 2017). Thus, this review is not comprehensive but tries to focus on experimental approaches and concepts to show how regulation by 3′ UTRs is accomplished.

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