Elevated homocysteine levels are associated with a variety of vascular diseases. Specifically, hyperhomocysteinemia is a risk factor for coronary artery disease, cerebrovascular disease, and peripheral arterial disease. Laboratory-based strategies for its detection and quantification have evolved to meet the increasing need for accuracy in risk prediction. Although new technologies have been developed over the past 2 decades that have enhanced the precision of measurement, universal guidelines for circulating homocysteine determination remain lacking.