15-deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)) has been known to display multifaceted cellular functions, including anti-inflammatory and cytoprotective effects. However, depending on the concentrations and intracellular microenvironment, this cyclopentenone prostaglandin can exert opposite effects. Because of the alpha,beta-unsaturated carbonyl moiety present in its cyclopentenone ring structure, 15d-PGJ(2) can act as a Michael reaction acceptor and readily interacts with critical cellular nucleophiles, such as cysteine thiol groups in proteins. Many of the biological effects induced by 15d-PGJ(2) involve redox-transcription factors as the potential targets. Thus, 15d-PGJ(2) can modulate the transcriptional activities of nuclear factor-kappaB (NF-kappaB), activator protein-1 (AP-1), nuclear factor-erythroid 2p45 (NF-E2)-related factors (Nrf2), hypoxia inducible factor (HIF), etc. 15d-PGJ(2) is also well known as an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARgamma). However, the regulation of the aforementioned redox-sensitive transcription factors by 15d-PGJ(2) is not necessarily mediated via PPARgamma activation, but rather involves covalent modification or oxidation of their critical cysteine residues acting as a redox-sensor. This commentary describes the biological and physiological functions of 15d-PGJ(2) and underlying biochemical and molecular mechanisms with emphasis on the modulation of redox-sensitive transcription factors and their regulators.