Breast cancers (BCs) typically express estrogen receptors (ERs) but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers. Display omitted •Anti-estrogen therapies selectively enrich for BCSCs and activate Notch signaling•Notch pathway activation and ALDH1 predict for anti-estrogen treatment failure•Targeting of Notch4 reduces the population of BCSCs•Notch inhibitors might prevent relapse or overcome resistance in ER+ tumors Breast cancers frequently develop resistance to anti-estrogen treatment, which makes it imperative to understanding how therapy resistance develops. Here, Simões et al. show that combining standard anti-estrogen therapies with anti-Notch4 drugs targeting breast cancer stem cells should improve treatment of ER+ breast cancer patients by preventing relapse due to therapy resistance.