Many estrogen receptor-positive breast cancers respond well initially to endocrine therapies, but often develop resistance during treatment with selective estrogen receptor modulators (SERMs) such as tamoxifen. We have reported that the 14-3-3 family member and conserved protein, 14-3-3ζ, is up-regulated by tamoxifen and that high expression correlated with an early time to disease recurrence. However, the mechanism by which tamoxifen up-regulates 14-3-3ζ and may promote the development of endocrine resistance is not known. Our findings herein reveal that the tamoxifen up-regulation of 14-3-3ζ results from its ability to rapidly down-regulate miR-451 that specifically targets 14-3-3ζ. The levels of 14-3-3ζ and miR-451 were inversely correlated, with 14-3-3ζ being elevated and miR-451 being at a greatly reduced level in tamoxifen-resistant breast cancer cells. Of note, down-regulation of miR-451 was selectively elicited by tamoxifen but not by other SERMs such as raloxifene or ICI182,780 (Fulvestrant). Increasing the level of miR-451 by overexpression, which decreased 14-3-3ζ, suppressed cell proliferation and colony formation, markedly reduced activation of HER2, EGFR, and MAPK signaling, increased apoptosis, and importantly, restored the growth inhibitory effectiveness of SERMs in endocrine-resistant cells. Opposite effects were elicited by miR-451 knock-down. Thus, we identify tamoxifen down-regulation of miR-451, and consequent elevation of the key survival factor 14-3-3ζ, as a mechanistic basis of tamoxifen-associated development of endocrine resistance. These findings suggest that therapeutic approaches to increase expression of this tumor suppressor-like microRNA should be considered to down-regulate 14-3-3ζ and enhance the effectiveness of endocrine therapies. Furthermore, the selective ability of the SERM tamoxifen but not raloxifene to regulate miR-451 and 14-3-3ζ may assist in understanding differences in their activities, as seen in the STAR breast cancer prevention trial and in other clinical trials.