Recent randomized controlled clinical trials failed to confirm a perceived beneficial effect on cardiovascular disease by hormone therapy. Given the huge amount of observational data, as well as experimental data both in humans and various animal species, there is reason to believe that female sex steroids, in particular estrogen, possess cardiovascular benefits. The type, dose, and mode of administration of exogenous sex steroids may modify and even negate the beneficial effects. The results of the randomized trials, especially the WHI, should encourage the scientific community to try to define a target population in which benefits outweigh harm, as it must be regarded as proven that any hormone therapy regimen given to any population will not reach that goal. The recent finding that transdermal estrogens, in contrast to oral preparations, do not seem to be associated with an increased risk of venous thrombosis is challenging. It would seem appropriate to conclude that estrogens prevent arteriosclerosis. On a long-term basis, however, other more rapid effects on the cardiovascular system could be negative. Such an assumption contributes to the explanation of the discordant results from cohort studies versus randomized trials. Admittedly the current picture is complex, but far from definitive, and should challenge us all to continue research in this area.