The aim of this review is to present a general overview of the relationships among homocysteine metabolism, polymorphism of the genes encoding homocysteine metabolism-related enzymes, and the nutrients influencing the plasma homocysteine level. Combining these factors creates a profile of an individual's susceptibility to complex diseases associated with hyperhomocysteinemia. Homocysteine is an amino acid derived from the demethylation of methionine. Hyperhomocysteinemia is associated with an increased risk of several complex diseases, including cardiovascular diseases. The level of plasma homocysteine depends on the combined effects of genetic and environmental factors. Polymorphisms of genes encoding homocysteine metabolism-related enzymes, such as methylenetetrahydrofolate reductase, methionine synthase, methionine synthase reductase, and cystathionine beta-synthase, influence plasma homocysteine concentration and thereby cardiovascular health. On the other hand, homocysteine metabolism may be modulated by dietary intake of the nutrients involved in homocysteine metabolism (ie, folates, vitamin B(6), and vitamin B(12)). Thus, the appropriate health-promoting doses of these nutrients may vary among certain groups of individuals, depending on their genotypes and other risk factors for complex diseases. Better understanding of the relationship between genotype and nutrition influencing the plasma total homocysteine level and cardiovascular health may improve the cardiovascular diagnostic tests (ie, measurement of biologic markers). It could be possible to define the level of progression, severity, and susceptibility to disease much earlier than it is done now. In conclusion, the introduction of combined dietary and pharmacologic treatment would be possible at the initial stages of disease.