Messenger RNA decay is a critical mechanism to control the expression of many inflammation- and cancer-associated genes. These transcripts are targeted for rapid degradation through AU-rich element (ARE) motifs present in the mRNA 3' untranslated region (3'UTR). Tristetraprolin (TTP) is an RNA-binding protein that plays a significant role in regulating the expression of ARE-containing mRNAs. Through its ability to bind AREs and target the bound mRNA for rapid degradation, TTP can limit the expression of a number of critical genes frequently overexpressed in inflammation and cancer. Regulation of TTP occurs on multiple levels through cellular signaling events to control transcription, mRNA turnover, phosphorylation status, cellular localization, association with other proteins, and proteosomal degradation, all of which impact TTP's ability to promote ARE-mediated mRNA decay along with decay-independent functions of TTP. This review summarizes the current understanding of post-transcriptional regulation of ARE-containing gene expression by TTP and discusses its role in maintaining homeostasis and the pathological consequences of losing TTP expression.