Carotid artery disease, the primary trigger of ischaemic cerebrovascular events including stroke, causes major morbidity, mortality and healthcare costs worldwide. Still, treatment is based on criteria established in the 90s that do not take into account the molecular evolution we have witnessed since, nor the introduction of new medication, leading to remarkably high unnecessary surgical treatment while missing most patients at risk. TAXINOMISIS will provide novel disease mechanism-based stratification for carotid artery disease patients to address the needs for stratified and personalised therapeutic interventions in the current era. This will be achieved through (1) the dissection of mechanisms mediating carotid artery disease, and identification of susceptibility and protection factors of plaque erosion and/or rupture using longitudinal cohorts and multi-omics, (2) the definition of distinct disease phenotypes and endotypes, and generation of molecular fingerprints of high versus low-risk states through systems medicine, (3) the development of a multilevel risk prediction model of the symptomatic plaque incorporating new biomarkers and advanced imaging, implemented in a software, to assist patient stratification and clinical decision making, (4) the development of novel pharmacogenomics solutions based on lab-on-a-chip technology to support personalized treatment, (5) the evaluation of the new risk prediction model and lab-on-a-chip device in a prospective observational clinical study, and (6) the assessment of regulatory, cost-effectiveness and ethical issues towards the implementation and commercialization of the programme’s outcomes. TAXINOMISIS has therefore the potential to rationally change the current state-of-the-art in the stratification of patients with carotid artery disease by reducing unnecessary operations, refining medical treatment and opening up new avenues for therapeutic intervention, while strengthening the European biotechnology sector.