Cyclooxygenase (COX)-2 enzyme catalyzes the rate-limiting step of prostaglandin formation in pathogenic states, and overexpression of COX-2 occurs at multiple stages of colon carcinogenesis, allowing elevated prostaglandin synthesis to occur in the tumor microenvironment. In normal cells, COX-2 expression levels are potently regulated at the posttranscriptional level through various RNA sequence elements present within the mRNA 3' untranslated region (3'UTR). A conserved AU-rich element functions to target COX-2 mRNA for rapid decay and translational inhibition through association with various RNA-binding proteins to influence the fate of COX-2 mRNA. The 3'UTR contains alternative polyadenylation signals that result in a shortened 3'UTR and loss of regulatory elements. Specific microRNAs have been identified to bind regions within the COX-2 3'UTR and control COX-2 expression. Recent evidence demonstrates the functional significance of the COX-2 3'UTR and how improper recognition of the 3'UTR can contribute to COX-2 overexpression in colorectal cancer.