Cardiovascular disease (CVD) is the number one cause of morbidity and mortality in men and women worldwide. According to the WHO, by 2015, almost 20 million people will die from CVD each year. It is well established that men and women differ not only in baseline cardiac parameters, but also in the clinical presentation, diagnosis and treatment outcomes of CVD. Women tend to develop heart disease later in life than men. This difference has been attributed to the loss of estrogen during the menopausal transition; however, the biological explanations for the sexual dimorphism in CVD are more complex and seem unlikely to be due to estrogen alone. The current controversy that has arisen regarding the effects of HRT on CVD in women is a case in point. In this review, the sex-based differences in cardiac (patho-) physiology are discussed with emphasis on the impact of sex hormones, hormone receptors and diet on heart disease.