Increased levels of plasma total homocysteine (tHcy) can be caused by genetic mutations, vitamin deficiencies, renal and other diseases, and numerous drugs. Raised tHcy also correlate with increasing age, and are associated with laboratory evidence of atherogenesis (e.g. endothelial dysfunction) and thrombosis, and with epidemiological evidence of an increased risk of atherothrombotic vascular disease, including ischemic stroke. The association between raised tHcy and increased risk of ischemic stroke is independent of other known vascular risk factors and is biologically plausible; however, randomized controlled trials have not revealed a causal relationship. The recently published Vitamins In Stroke Prevention (VISP) trial identified no significant reduction in the relative risk of stroke by lowering tHcy with B-vitamin therapy among 3,680 patients with recent ischemic stroke. It did not, however, reliably exclude a modest but important reduction of up to 20% in relative risk of stroke. Currently, there is insufficient evidence to confirm that homocysteine is a modifiable causal risk factor for stroke, or to recommend routine screening for, or treatment of, raised tHcy concentrations with folic acid and other vitamins, to prevent ischemic stroke.