In patients with advanced-stage breast cancer, recurrent genomic structural rearrangements can result in fusion proteins. To determine the role of genomic structural rearrangements in resistance to endocrine therapy, a retrospective analysis was conducted in samples derived from primary tumours and matched metastases of patients with metastatic oestrogen receptor (ER)-positive breast cancer. Among the genomic rearrangements affecting ESR1, which encodes the ER, events leading to the generation of nine ESR1 fusion proteins were identified as recurrent, albeit rare, events, present in at least 1% of metastatic ER-positive breast cancers. All fusions resulted in a breakpoint in or near ESR1 intron 6, leading to a defective ligand binding domain, and probably reflect secondary resistance to endocrine therapy.