Rationale: There is strong epidemiological evidence for an association between acute and chronic infections and the occurrence of atherosclerotic cardiovascular disease (ASCVD). The underlying pathophysiological mechanisms remain unclear. Monocyte-derived macrophages are the most abundant immune cells in atherosclerotic plaques. It has recently been established that monocytes/macrophages can develop a long-lasting pro-inflammatory phenotype after brief stimulation with micro-organisms or microbial products, which has been termed trained immunity. Objective: To assess whether trained immunity mediates the link between infections and ASCVD. Methods and Results: Brief exposure of monocytes to various micro-organisms results in the development of macrophages with a persistent pro-inflammatory phenotype: this represents a de-facto nonspecific innate immune memory which has been termed trained immunity. This is mediated by epigenetic reprogramming at the level of histone methylation, and a profound rewiring of intracellular metabolism. Although this mechanism offers powerful protection against reinfection, trained macrophages display an atherogenic phenotype in terms of cytokine production and foam cell formation. Trained monocytes are present up to three months following experimental infection in humans. Moreover, a trained immunity phenotype is present in patients with established atherosclerosis. Conclusions: We propose that trained immunity provides the missing mechanistic link that explains the association between infections and atherosclerosis. Therefore, pharmacological modulation of trained immunity has the potential to prevent infection-related ASCVD in the future.