Hyperhomocysteinemia (Hhcy) is an established risk factor for various pathologies including arterial vascular disease and venous thrombosis, congenital malformations and other pregnancy complications, and dementia. Homocysteine remethylation, transsulfuration, and export to the blood/extracellular compartment determine homocysteine concentrations. Any disturbance in these routes may lead to Hhcy and potentially increase risk of disease. In this report, we aim to review all known polymorphisms involved in homocysteine and B-vitamin metabolism that have been assessed for their effect on tHcy. In the last section, we summarize the polymorphisms, for which the obtained data provides evidence for their involvement in Hhcy at the population level, and discuss how to continue our search for genetic determinants of tHcy.