This article addresses the various aspects concerning gender dissimilarities in the cardiovascular system. It examines sex differences in the genetic susceptibility to cardiovascular disease (CVD) development or outcome: with the presence of either XX or XY chromosomes, every cell is sexually differentiated and there exist postpuberal differences between male and female cardiovascular systems. The main action mechanisms of sex steroid hormones are discussed, mainly as to testosterone (Te) in men and 17beta-estradiol (E2) and progesterone (Pro) in women. In women, susceptibility to CVD is known to increase in the postmenopausal period, when the ovarian hormone function expires. Some concepts of the sex-based differences in anatomy and physiology are also explained. Although they have the same structural elements, women and men use them in a different way to guarantee cardiovascular system homeostasis. Some examples of differences between men and women in pathological cardiovascular function are given. A further important issue regards the prevalence and role of cardiovascular risk factors in the two genders. Compared to boys of the same age, adolescent girls and premenopausal women have a more favorable risk profile: lower blood pressure (BP), less atherogenic lipid profile, and lower prevalence of cardiovascular risk factors. Women develop CVD later than men and diabetic women have a considerably higher mortality rate compared to men of the same age. Finally, there exist several clinically significant differences between men and women as to prevalence, presentation, management and outcome of CVD. Clinical peculiarities related to gender in presentation of some CVDs, such as coronary heart disease (CHD), stroke and heart failure, are described. We are absolutely convinced that only an accurate knowledge of the sex-specific pathophysiology may allow determination of the appropriate diagnostic instruments and to implement tailored treatments of CVD in men and women.