Based on the results of a French cohort of postmenopausal women, it has been claimed that micronized progesterone does not enhance breast cancer risk. The impact of reproductive factors on breast cancer risk and a high prevalence of occult breast carcinomas at the time of menopause suggest an involvement of endogenous progesterone in the development of breast cancer. High mammographic density in the luteal phase and during treatment with estrogen/progestogen combinations reflect a change in the composition of mammary stroma and an increased water accumulation in the extracellular matrix which is caused by hygroscopic hyaluronan-proteoglycan aggregates. Proteoglycans are also involved in the regulation of proliferation, migration, and differentiation of epithelial cells and angiogenesis, and may influence malignant transformation of breast cells and progression of tumors. Reports on a lack of effect of estrogen/progesterone therapy on breast cancer risk may be rooted in a selective prescription to overweight women and/or to the very low progesterone serum levels after oral administration owing to a strong inactivation rate. The contradictory results concerning the proliferative effect of progesterone may be associated with a different local metabolism in normal compared to malignant breast tissue. Similar to other progestogens, hormone replacement therapy with progesterone seems to promote the development of breast cancer, provided that the progesterone serum levels have reached the threshold for endometrial protection.