The AU-rich element (ARE) was discovered in 1986 as a conserved mRNA sequence found in the 3′ untranslated region of the TNF-α transcript and other transcripts encoding cytokines and inflammatory mediators. Shortly thereafter, the ARE was shown to function as a regulator of mRNA degradation, and AREs were later shown to regulate other posttranscriptional mechanisms such as translation and mRNA localization. AREs coordinately regulate networks of chemokine, cytokine, and growth regulatory transcripts involved in cellular activation, proliferation, and inflammation. ARE-mediated regulation is carried out by a host of ARE-binding proteins, whose activity is regulated in a cell type and activation-dependent manner. The last 25 years of ARE research has offered insight into the mechanisms and regulation of ARE-mediated mRNA decay, and has provided a road map for the discovery of additional mRNA regulatory motifs. The future of ARE research will transition from a discovery phase to a phase focused on translating basic biological findings into novel therapeutic targets. Our understanding of ARE-mediated gene regulation and posttranscriptional control has implications for many fields of study including developmental biology, neuroscience, immunobiology, and cancer biology.