Infections and vaccinations can induce long-term enhanced responses of innate immune cells to heterologous stimuli, establishing a de facto innate immunological memory termed trained immunity. Monocytes exposed to the Bacillus Calmette-Guerin (BCG) vaccine, have a trained immunity phenotype, characterized by an increased biosynthesis of different lipid mediators (LMs) derived from long-chain polyunsaturated fatty acids (PUFAs). Pharmacological and genetic approaches showed that long-chain PUFA synthesis and lipoxygenase (LOX)-derived LMs are crucial for the BCG trained immunity responses of human monocytes. Furthermore, monocytes of healthy individuals vaccinated with BCG are enriched in 12-LOX products. The elucidation of the lipid metabolic pathways that promote innate immune memory contributes to our understanding of trained immunity and may help identify therapeutic tools and targets for the modulation of innate immune responses. ### Competing Interest Statement MGN is a scientific founder of TTxD. The remaining authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.