Overexpression of the enzyme COX-2 (cyclo-oxygenase-2) is associated with various pathophysiological conditions, including inflammatory diseases and different cancers. Increased synthesis of COX-2 in fetal membranes and the myometrium is also linked with the onset of term and preterm labour. COX-2 gene regulation is controlled at various levels including gene transcription and post-transcriptional events. The present article focuses on the complexity of COX-2 gene regulation and reviews current concepts that highlight: (i) transcription of COX-2 is induced rapidly and transiently in response to a plethora of stimuli; (ii) COX-2 mRNA stability and translational efficiency is governed by multiple regulatory elements within the 3'-untranslated region; (iii) specific microRNAs and RNA-binding proteins influence COX-2 mRNA stability; and (iv) regulation of COX-2 involves alternative polyadenylation.