The link between vascular disease and elevated homocysteine levels has been recognized for more than 30 years, and an association with moderately elevated levels has been suspected for 20 years. The initial investigations were case series, cross-sectional, and case-control studies. Those studies consistently suggest a strong positive relationship between moderate hyperhomocysteinemia and risk of vascular disease. However, a major limitation of these types of study design is that the possibility of elevated homocysteine levels being influenced by the disease or its treatment cannot be ruled out. In case-control studies there is always concern about the appropriateness of the control group. These issues pose much less of a problem in prospective designs. Prospective studies also offer the opportunity to study various manifestations of cardiovascular disease at the same time. However, prospective studies tend to be more expensive and time-consuming, perhaps explaining the smaller number of prospective studies and why the first was not published until 1992. The distinct limitations and advantages of prospective studies are also reviewed.