Cardiovascular disease (CVD) mortality and morbidity is predicted to increase in Europe and worldwide in the next decades due to aging and the rise of diabetes and obesity. The link between metabolic and inflammatory disease is getting stronger, raising hopes for novel therapeutic targets to be exploited clinically. Clinical evidence generated by the Academic partners of the Athero-B-Cell Consortium demonstrates that CVD is associated with pro- and anti-atherogenic B cell responses. We aim to use existing proteomic, transcriptomic and miRNA data generated from large-scale clinical studies in previous EU-funded collaborative efforts to decipher the pathways that favor pro- and anti-atherogenic B cell functions in order to unravel a new set of therapeutic targets and refine potential vaccine strategies for CVD. The selection and validation of targets will be made possible by substantial technological advance achieved by the participating SMEs that are world leaders in the field of bioinformatics, genetic modification including humanised mouse models, and 3rd generation antisense drugs with locked nucleic-acid (LNA) design that are in Phase II human trials. Academia-led innovation includes high-resolution methodologies such as CyTOF and ImageStream to interrogate available samples from clinical trials and the ability to validate the targets of interest in accredited models of CVD. The validation in vivo and in vitro of such targets will feed into the SME pipeline accelerating the process of drug discovery. The recent clinical success of 3rd generation antisense drugs underscores the advantage of the Athero-B-Cell approach: the seamless transition from validation tools to clinical applications. Harnessing protective or abating unwanted B cell responses has the potential to improve health, innovation and competitiveness of European SME and Academia, while shedding light on the pathogenesis of CVD, the world's biggest killer.