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There are substantial gender differences in the pattern, severity and treatment of heart disease independent of environmental risk factor exposure.There has also been a common misperception that CVD is not a real problem for women.As a consequence, there has been considerable interest in the potential role of sex hormones in heart disease, particularly the potential protective effects of estrogen.However, the failure of the recent clinical randomized trials to show a cardio-protective effect for estrogen has refocused interest on the role of hormones and genes in cardiovascular biology and disease.Over the last decade, compelling evidence has emerged that sex differences in our vessels are not only determined by gender-related differences in sex steroid levels but also by genetic, gender specific tissue and cellular characteristics which mediate sex-specific responses to a variety of stimuli.This gender dependent regulation may have important implications for understanding the basis of the gender gap in heart disease and may eventually lead to the development of sex-specific treatments.This lecture will summarize the current thinking for the role of hormones and genes in gender differences in coronary heart disease and cardiovascular biology and includes recent data from our group that supports the theory that the genes on the Y chromosome contributes to cardiovascular mortality.