Several types of exposures can cause acute or chronic inflammatory reactions in the lungs often leading to asthma, pulmonary fibrosis, chronic obstructive pulmonary disease (COPD), acute lung injury, lung cancer, and other deleterious health outcomes. Current therapy, with inhaled or oral glucocorticoids, successfully targets inflammation but also produces adverse effects that limit their enthusiastic use. Accordingly, the need remains for interventions that are safer and more effective. Nitrated fatty acids (NFAs) are highly electrophilic and are produced endogenously by non-enzymatic reactions of nitric oxide with conjugated unsaturated fatty acids. The literature indicates that NFAs are detected in humans at the nanomolar range and are produced more robustly under inflammatory conditions. Recent studies on novel NFAs report antiinflammatory, antioxidant, and antifibrotic effects, while also acting as partial agonists of peroxisome proliferator-activated receptor-gamma (PPAR-γ). Furthermore, these functions of NFAs occur via reversible electrophilic alkylation of cysteine residues and regulation of antiinflammatory, antioxidant signaling through modulation of transcription factors, including nuclear factor E2-related factor 2 (Nrf2), PPAR-γ, and NF-κB. Here, we review and update the role of NFA signaling mechanisms and their therapeutic potential in various lung diseases. As NFAs display strong electrophilic interaction with multimechanistic pathways, they can be considered promising drug candidates for challenging lung diseases.Copyright © 2020 Elsevier Inc. All rights reserved.