Atherothrombosis is the primary cause of death in Western countries. The cellular and molecular mechanisms underlying atherosclerosis remain widely unknown. The complex nature of atherosclerotic cardiovascular diseases demands the development of novel technologies that enable discovery of new biomarkers for early disease detection and risk stratification, which may predict clinical outcome. In this review, we outline potential sources and recent proteomic approaches that could be applied in the search of novel biomarkers of cardiovascular risk. In addition, we describe some issues raised in relation to the application of proteomics to blood samples, as well as two novel emerging concepts, such as peptidomics and population proteomics. In the future, the use of high-throughput techniques (proteomic, genomics and metabolomics) will potentially identify novel patterns of biomarkers, which, along with traditional risk factors and imaging techniques, could help to target vulnerable patients and monitor the beneficial effects of pharmacological agents.