The cyclopentenone prostaglandins PGA₂, PGA₁, and PGJ₂ are formed by dehydration within the cyclopentane ring of PGE₂, PGE₁, and PGD₂. PGJ₂ is metabolized further to yield Δ¹²‐PGJ₂ and 15‐deoxy‐Δ^12,14‐PGJ₂ (15d‐PGJ₂). Various compounds within the cyclopentenone prostaglandin family possess potent anti‐inflammatory, anti‐neoplastic, and anti‐viral activity. Most actions of the cyclopentenone prostaglandins do not appear to be mediated by binding to G‐protein coupled prostanoid receptors. Rather, the bioactivity of these compounds results from their interaction with other cellular target proteins. 15‐deoxy‐Δ^12,14‐PGJ₂ is a high affinity ligand for the nuclear receptor PPARγ and modulates gene transcription by binding to this receptor. Other activities of the cyclopentenone prostaglandins are mediated by the reactive α,β‐unsaturated carbonyl group located in the cyclopentenone ring. The transcription factor NF‐κB and its activating kinase are key targets for the anti‐inflammatory activity of 15d‐PGJ₂, which inhibits NF‐κB‐mediated transcriptional activation by PPARγ‐dependent and independent molecular mechanisms. Other cyclopentenone prostaglandins, such as Δ⁷‐PGA₁ and Δ¹²‐PGJ₂, have strong anti‐tumor activity. These compounds induce cell cycle arrest or apoptosis of tumor cells depending on the cell type and treatment conditions. We review here recent progress in understanding the mechanisms of action of the cyclopentenone prostaglandins and their possible use as therapeutic agents. © 2001 John Wiley & Sons, Inc. Med Res Rev, 21, No. 3, 185–210, 2001