While the benefits of progestins in hormonal replacement therapy are well recognized as far as endometrial protection is concerned the data on breast tissue and the cardiovascular system are contentious. Following the Women's Health Initiative study, the Million Women Study and The Women's International Study of Long-duration (O)estrogen after Menopause the question can be raised: When dealing with optimal hormonal therapy after the menopause, is the progestin component accepted here on sufferance or is it desired? The answer is partly made up by the fact that the recent epidemiological data may have been not only wrongly translated in relation to the clinical settings, but also to the whole class of therapies. The various progestins available for hormonal therapy exert different partial effects at cellular level according to the biochemical composition. Due to the structural differences the progestins result in a variety of tissue transforming changes as well as metabolic and hemostatic changes. Since no single test or algorithm presently serves as golden standard for all desired hormonal effects the least changes or no changes from the premenopausal physiology may often be advantageous. In our opinion targeting this goal includes a sustained desire for an estrogen/progestin combination as optimal future hormone therapy. Moreover the strategy not only includes evaluation of the specific steroidal formula, but also a titration of the dose and choosing the optimal route of administration. With special reference to cardiovascular disease this review therefore makes a plea for differentiating between the array of chemically and functionally distinct progestins used therapeutically after the menopause in combination therapy.