We sought to uncover genetic drivers of hormone receptor–positive (HR +) breast cancer, using a targeted next-generation sequencing approach for detecting expressed gene rearrangements without prior knowledge of the fusion partners. We identifi ed intergenic fusions involving driver genes, including PIK3CA, AKT3, RAF1, and ESR1, in 14% (24/173) of unselected patients with advanced HR + breast cancer. FISH confi rmed the corresponding chromosomal rearrangements in both primary and metastatic tumors. Expression of novel kinase fusions in nontransformed cells deregulates phosphoprotein signaling, cell proliferation, and survival in threedimensional culture, whereas expression in HR + breast cancer models modulates estrogen-dependent growth and confers hormonal therapy resistance in vitro and in vivo. Strikingly, shorter overall survival was observed in patients with rearrangement-positive versus rearrangement-negative tumors. Correspondingly, fusions were uncommon (<5%) among 300 patients presenting with primary HR + breast cancer. Collectively, our fi ndings identify expressed gene fusions as frequent and potentially actionable drivers in HR + breast cancer. SIGNIFICANCE: By using a powerful clinical molecular diagnostic assay, we identifi ed expressed intergenic fusions as frequent contributors to treatment resistance and poor survival in advanced HR + breast cancer. The prevalence and biological and prognostic signifi cance of these alterations suggests that their detection may alter clinical management and bring to light new therapeutic opportunities.