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25 p.-3 fig.-3 tab., Protein lipoxidation is a non-enzymatic post-translational modification that consists of the covalent addition of reactive lipid species to proteins. This occurs under basal conditions but increases in situations associated with oxidative stress. Protein targets for lipoxidation include metabolic and signalling enzymes, cytoskeletal proteins, and transcription factors, among others. There is strong evidence for the involvement of protein lipoxidation in disease, including atherosclerosis, neurodegeneration, and cancer. Nevertheless, the involvement of lipoxidation in cellular regulatory mechanisms is less understood. Here we review basic aspects of protein lipoxidation and discuss several features that could support its role in cell signalling, including its selectivity, reversibility, and possibilities for regulation at the levels of the generation and/or detoxification of reactive lipids. Moreover, given the great structural variety of electrophilic lipid species, protein lipoxidation can contribute to the generation of multiple structurally and functionally diverse protein species. Finally, the nature of the lipoxidised proteins and residues provides a frameshift for a complex interplay with other post-translational modifications, including redox and redox-regulated modifications, such as oxidative modifications and phosphorylation, thus strengthening the importance of detailed knowledge of this process., Work at DPS laboratory is supported by RTI2018-097624-B-I00 from Agencia Estatal de Investigación, MICINN/ERDF, and RETIC ARADYAL RD16/0006/0021 from ISCIII/ERDF, Spain Work at CMS laboratory (including I.C.M. and O.L.) is supported by funding from the European Union’s Horizon 2020 research and innovation programme under Marie Sklodowska-Curie grant agreement No 847419 (MemTrain). Á.V.P. and P.G.J. are the recipients of predoctoral contracts BES-2016-076965 and PRE2019-088194, respectively, from MICINN, Spain.