The female sex hormones, estrogens (E) and progesterone (P) are major determinants of postnatal mammary gland development and are thought to promote breast carcinogenesis. How do they impact on the human breast? The most widely used models to study E and P signaling are hormone receptor positive breast cancer cell lines. However, it is unclear to what extent they provide insights into the breast tissue molecular pathophysiology. The study (Tamara T., Sflomos G et al., Science Translational Medicine, 2013, Vol. 5, Issue 182, p. 182) presents and validates a novel ex vivo culture model based on tissue microstructures from fresh human reduction mammoplasty specimens. For the first time, physiological hormone action can be studied in a human model and new opportunities to unravel hormone action open up. The work revealed Progesterone/RANKL axis as a major driver of cell proliferation in the adult human breast with potential clinical implications for breast cancer patients. Current knowledge about the mechanisms by which female reproductive hormones control mammary gland development and breast carcinogenesis stem mainly from animal studies. In particular, the mouse model, in which genetic tools can be combined with powerful tissue recombination techniques, has been instrumental in revealing that epithelial estrogen receptor (ERα) signaling controls pubertal gland development whereas progesterone receptor (PR) signaling is the major proliferative stimulus in the adult mouse mammary gland. Across species, 30-50% of the breast epithelial cells express the ERα and PR. The mouse model revealed that at the cellular level, hormone action relies largely on paracrine signaling. In particular, receptor activator of nuclear factor kappaB ligand (RANKL) is a central mediator of PR-induced cell proliferation. RANKL, a transmembrane type II protein is a member of the tumor necrosis factor superfamily and signals through its receptor RANK (Figure 1). Upon RANKL binding, RANK receptor elicits activation of a signaling cascade important for mammary gland development and tumorigenesis. Epidemiological studies have linked menstrual cycles to breast cancer risk and it is conceivable that the associated peaks of serum progesterone levels could lead to RANKL induction and subsequent cell proliferation. Such a scenario has clinical implications because drugs that target PR/RANKL have been developed to treat reproductive disorders and bone diseases, respectively. If the same pathway is involved in human breast carcinogenesis, these drugs may be used for breast cancer prevention in high-risk patients who are premenopausal to interfere with tumor promoting effects of menstrual cycles.