Atherosclerosis is a chronic inflammatory disease leading to cardiovascular complications responsible for a high level of morbidity and mortality worldwide. Increasing evidence tends to hold that humoral and cellular immune responses are a key component of human atherosclerosis development. Since the last decade, auto-antibodies have been identified as active mediators of cardiovascular disease, some presenting protective effects whereas others act as potential risk factors. This review presents an overview of the most relevant auto-antibodies with regards to their respective cardiovascular prognostic value in acute coronary syndrome, stroke and cardiomyopathies, and their potential pathophysiologic implication in atherogenesis. Insights in the mechanisms of action of the auto-antibodies show that they commonly modulate the innate immune system towards a pro- or anti-inflammatory response and/or affect the regulation of basal heart rate. The increased understanding of the auto-antibodies functional properties has led to the development of new therapeutic approaches targeting the innate immune system or the epitope-binding site. Some of these auto-antibodies have been reported to be independent prognostic factors of poor disease outcome. In addition to conventional risk factors, these autoantibodies could be helpful biomarkers to increase the sensitivity and specificity of the cardiovascular stratification tools, improving prognostication, diagnostic and the use of specific therapy.