A reaction of arachidonic acid with the nitrogen dioxide radical (NO₂) or its precursors (peroxynitrite, nitrous acid, nitrogen trioxide) generates a group of nitro lipids named nitroeicosanoids. A distinct feature of this reaction is abundant formation of four trans isomers of arachidonic acid (TAA) via reversible addition of the NO₂ radical to the arachidonic acid cis double bonds. This cis–trans isomerization is biologically relevant because many pathologies that involve NO formation such as inflammation, hyperoxia, hypercapnia or exposure to cigarette smoke increase the TAA levels in cells, tissues and in the systemic circulation. Inflammatory conditions have been known to stimulate formation of a variety of oxidized lipids from unsaturated fatty acid precursors via lipid peroxidation mechanisms; however, nitration-dependent cis–trans-isomerization of arachidonic acid is a characteristic process for NO₂. TAA are likely to function as specific and selective biomarkers of the pathologic conditions that define nitro-oxidative stress. Diet independent biosynthesis of trans fatty acids as a result of disease is our new observation. In the past, experimental feeding and clinical studies have supported the concerns that dietary trans fatty acids are cardiovascular risk factors, however, clinical consequences of the endogenous formation of trans fatty acids are not known but potentially important given available studies on TAA. This review aims to summarize the emerging role of TAA as a unique group of biomarkers that target microcirculation and other systems. A biological mechanism that generates endogenous trans fatty acids poses new challenges for pharmacologic intervention and we suggest approaches that may limit TAA effects.