Approximately 70% of breast cancers are oestrogen receptor α (ER) positive, and are, therefore, treated with endocrine therapies. However, about 25% of patients with primary disease and almost all patients with metastases will present with or eventually develop endocrine resistance. Despite the magnitude of this clinical challenge, the mechanisms underlying the development of resistance remain largely unknown. In the past 2 years, several studies unveiled gain-of-function mutations in ESR1, the gene encoding the ER, in approximately 20% of patients with metastatic ER-positive disease who received endocrine therapies, such as tamoxifen and aromatase inhibitors. These mutations are clustered in a 'hotspot' within the ligand-binding domain (LBD) of the ER and lead to ligand-independent ER activity that promotes tumour growth, partial resistance to endocrine therapy, and potentially enhanced metastatic capacity; thus, ER LBD mutations might account for a mechanism of acquired endocrine resistance in a substantial fraction of patients with metastatic disease. In general, the absence of detectable ESR1 mutations in patients with treatment-naive disease, and the correlation between the frequency of patients with tumours harbouring these mutations and the number of endocrine treatments received suggest that, under selective treatment pressure, clonal expansion of rare mutant clones occurs, leading to resistance. Preclinical and clinical development of rationale-based novel therapeutic strategies that inhibit these ER mutants has the potential to substantially improve treatment outcomes. We discuss the contribution of ESR1 mutations to the development of acquired resistance to endocrine therapy, and evaluate how mutated ER can be detected and targeted to overcome resistance and improve patient outcomes.