There is an accumulating body of evidence linking estrogen receptor-alpha (ER-alpha) gene polymorphisms with variation in cardiovascular risk factors or disease. The ER-alpha IVS1-397 T/C (PvuII), IVS1-351 A/C (XbaI) and the promoter region TA repeat polymorphisms have received the most attention. If ER-alpha genetic variants identify women at high risk for cardiovascular events, this information could be used to improve clinical decisions regarding the use of hormone replacement therapy (HRT). More detailed haplotype and genome-wide studies of many of the major HRT clinical trial cohorts are currently underway and these efforts promise to clarify many outstanding issues concerning estrogen action and cardiovascular disease.