Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum of ESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.