Many studies have shown that raised serum/plasma levels of total homocysteine (tHcy) increase the risk of coronary, cerebral, and peripheral artery disease. The risk associated with hyperhomocysteinemia appears to be concentration-dependent and not attributable to traditional risk factors. tHcy are increased as a result of age, male gender, impaired renal function, low vitamin B and folate intake, and genetically-determined defects of the enzymes involved in homocysteine metabolism. Conflicting results have been reported in genetic, observational and experimental studies on relationship between tHcy and these atherothrombotic disease. In facts in individuals with tHcy concentrations are increased for genetic origin there is no clear evidence fore causal role of tHcy in the pathogenesis of atherosclerosis disease and positive association between tHcy and cardiovascular disease observed in many, but not all clinical-epidemiologic studies does not prove causality. Despite increasing recognition of hyperhomocysteinemia as a risk factor for arterial thrombosis disease, irrefutable proof that mild hyperhomocysteinemia contributes directly to the pathogenesis of atherothrombosis will come if interventions to lower total homocysteine reduce cardiovascular events.