Progestogens are commonly used in hormone replacement therapy, normally as opponents of estrogen to protect the endometrium from hyperplasia and cancer. While these benefits of endometrial protection are well recognized, the data related to the effect of progestogens on breast tissue and the cardiovascular system are conflicting. It has been demonstrated that, according to the type of progestogen used, and the dose and duration of its application, a predominant proliferative effect may be observed in human breast cells. As far as breast cancer is concerned, most epidemiological studies suggest no difference in risk between therapy with estrogens alone or estrogens combined with progestogens, but recent data do indicate an increased risk with combined therapy. When the cardiovascular risk factors are considered, some progestogen molecules with a higher androgenic potency than others attenuate the beneficial effects of estrogens on both the lipid profile and vasomotion. On the other hand, the epidemiological data on primary prevention do not suggest any negative effect of the progestogens administered together with estrogens on cardiovascular morbidity or mortality. Recent results have questioned the cardioprotective effect of hormone replacement therapy in women with established coronary heart disease. It has been suggested that the lack of a secondary preventive effect by hormone replacement therapy may be due to the progestogens selected. The effect on osteoporosis is also the subject of debate, with some progestogens having a neutral effect on bone mineral density and others producing a marked improvement. Awareness of the classic contraindications of hormone replacement therapy and selection of molecules devoid of estrogenic, androgenic or glucocorticoid effect should allow greater use of the progestogens without any major drawback.