Estrogen replacement may reduce the risk of several diseases in postmenopausal women, but progestins may attenuate these benefits. While the benefits of progestins use in hormonal replacement therapy are well recognized as far as endometrial protection is concerned, their risks and drawbacks have generated controversial opinion. Several risk are attributed to progestins as a class-effect; however, the progestogens used in hormonal replacement therapy have varying pharmacological properties and do not induce the same side effects. Newly synthesized progestins (19-nor derivative) do not bind to the androgen receptor and do not exert androgenic side effect. Selection molecules devoing of estrogenic, androgenic or glucocorticoid effect should allow a larger use of the progestins in HRT without any major drawback.