The J series of cyclopentenone prostaglandins (PGs) such as 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)) are electrophilic lipid signaling mediators derived from the nonenzymatic dehydration of PGD(2), a major product of the cyclooxygenase pathway. The biological actions of 15d-PGJ(2) are attributed to its ability to form covalent adducts with thiol residues within specific signaling proteins, thus triggering redox-sensitive cell signaling pathways. One of the signaling pathways potently activated by 15d-PGJ(2) is the Keap1-Nrf2-ARE system, which has a well-appreciated role in protecting cells from endogenous and exogenous stresses as well as anti-inflammatory effects. In this review, we give an overview of the mechanisms by which 15d-PGJ(2) activates the Keap1-Nrf2-ARE system, focusing particularly on the role of Keap1 in sensing electrophilic stress. In addition, the Nrf2-dependent anti-inflammatory and cytoprotective effects of 15d-PGJ(2) are discussed.