Systemic and local signals must be integrated by mammary stem and progenitor cells to regulate their cyclic growth and turnover in the adult gland. Here, we show RANK-positive luminal progenitors exhibiting WNT pathway activation are selectively expanded in the human breast during the progesterone-high menstrual phase. To investigate underlying mechanisms, we examined mouse models and found that loss of RANK prevents the proliferation of hormone receptor-negative luminal mammary progenitors and basal cells, an accompanying loss of WNT activation, and, hence, a suppression of lobuloalveologenesis. We also show that R-spondin1 is depleted in RANK-null progenitors, and that its exogenous administration rescues key aspects of RANK deficiency by reinstating a WNT response and mammary cell expansion. Our findings point to a novel role of RANK in dictating WNT responsiveness to mediate hormone-induced changes in the growth dynamics of adult mammary cells. Display omitted •Luminal progenitors are targets of progesterone in the adult human breast•Progesterone-induced expansion of mammary epithelial subsets requires RANK•RANK signaling targets WNT-responsive ER–PR– luminal progenitors and basal cells•RANK controls RSPO1, which rescues defective progenitor expansion in Rank-null state Cellular signals governing the WNT response are largely unknown despite the widely recognized function of this pathway in the control of stem and progenitor cells in diverse tissues. Khoka and colleagues describe RANK signaling as a requisite step for the expansion of ER–PR– adult mammary epithelial progenitors and acquisition of WNT responsiveness through its regulation of the WNT agonist R-SPONDIN1.