In the effort to explain gender-related differences of the cardiovascular system, the renin-angiotensin system experienced intensive exploration. Indeed, the development of hypertension as well as the progression of coronary artery disease and heart failure have two factors in common: (1) display distinct gender specific characteristics and (2) are enhanced by the renin-angiotensin system. It is therefore interesting to note that data from experimental animals, epidemiological surveys, and clinical investigations suggest that the components of the circulating as well as tissue-based renin-angiotensin system are markedly affected by gender. However, the issue is complicated by counter-regulatory effects of estrogen on the system with the substrate, on one hand, and the processing enzymes as well as the chief receptor, on the other hand. In fact, angiotensinogen is up-regulated particularly by oral administration of estrogen, whereas renin, angiotensin-converting enzyme (ACE), and AT-1 receptor are down-regulated by the hormone. While under well-defined experimental conditions the net effect of estrogen appears to result in suppression of the renin-angiotensin system, the clinical situation may be more complex. The judgment is further complicated by the difficulty in precisely measuring the activity of the system at the tissue level. Moreover, clinically relevant read-outs for the activity of the renin-angiotensin system may be regulated multifactorially or only indirectly affected by the system. Nevertheless, the undisputable, profound biochemical changes in the renin-angiotensin system related to the estrogen status allow speculation that such interaction explains some of the differences in the cardiovascular system of men and women.