High fasting plasma homocysteine levels (> 12 to 15 mumol/L) are commonly encountered in clinical practice and are associated with increased risk of atherothrombotic disease. Treatment with folic acid (1 to 5 mg/day) is inexpensive and effective in normalising plasma homocysteine levels. High plasma homocysteine levels after methionine loading (> 40 to 50 mumol/L) are also common and can be treated with pyridoxine-based regimens (50 to 250 mg/day). As compared with fasting plasma homocysteine levels, the association between high postmethionine loading plasma homocysteine levels and atherothrombotic disease has been less extensively studied. There is reasonable, but not clearly definitive, evidence that high plasma homocysteine levels are causally related to atherothrombotic disease. Results of randomised trials of homocysteine-lowering treatment with clinical end-points will be available in 4 to 6 years. At present, a reasonable policy for the practising clinician would be to consider homocysteine-lowering treatment in individuals at very high risk of atherothrombotic disease, such as patients with clinically manifest atherothrombotic disease with onset before 55 years of age, patients with end stage renal disease, and healthy subjects with a strong family history of early-onset atherothrombotic disease. Such a policy should be reassessed as the results of randomised trials become available.