Atherothrombosis remains a major cause of morbidity and mortality in the western world. The underlying processes associated with clinical expression of atherothrombosis include oxidative stress and proteolysis in relation to neovascularisation and intraplaque hemorrhages, leading to immuno-inflammatory response, cell death, and extracellular matrix breakdown. The complex biological multifactorial nature of atherothrombosis requires the development of novel technologies that allow the analysis of cellular and molecular processes responsible for the transition to disease phenotypes and the discovery of new diagnostic and prognostic biomarkers. In the present article, we have reviewed recent advances in the application of proteomic and metabolomic techniques to the study of atherothrombosis. We have focused on recent studies analyzing cells involved in hemo-thrombus formation (platelets, red blood cells, and polymorphonuclear cells), as well as tissues, tissue-conditioned media, and plasma of atherothrombotic patients. In the future, the application of these high-throughput technologies, along with imaging techniques, in systems biology approaches will help to individualize medicine.