Using natural, evolutionary selected, human sexual steroids, i.e. estradiol (E2) and progesterone (P4), for menopause hormone therapy (MHT) to avoid some of the risks associated with synthetic compounds, seems not only biologically plausible but has also been supported by safety data of a wide range of observational case-control and cohort studies. Randomized controlled trials (RCTs) are of limited validity, because of high drop-out rates in the placebo groups even in mostly asymptomatic women as demonstrated in the WHI combined CEE+MPA-arm. Data from well-designed observational studies, however, particularly in symptomatic climacteric patients, reflect much better the real-life situations of daily practice. Some examples of such newer post-WHI literature will be discussed in respect to long-term safety, suggesting that beside the consideration of the ‘window of opportunity’, the transdermal administration of E2 in combination with a neutral progestogen, preferably orally administered micronized P4, may be the safest option of MHT, minimizing the risks of breast cancer, cardiovascular disease, stroke, and venous thromboembolic events.