Today, the diagnosis of metastatic breast cancer is usually based on radiological findings, and therapeutic decisions are made by considering the pathological characteristics and predictive markers of the primary tumour. Accumulating evidence suggests that tumour characteristics, including estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2), are unstable through tumour progression. Several retrospective studies and, recently, two prospective studies have investigated the discrepancies in receptor status between primary tumours and the corresponding metastases in a total of 1773 patients (for ER) and 2845 patients (for HER2). Changes in ER and HER2 status in these studies range from 14.5% to 40% and from 0% to 37.5%, respectively. In the two prospective studies, a different diagnosis, usually non-malignant, was obtained in 3% and 9% of the cases, and the biopsy led to a treatment modification in about one out of seven patients. Here, we review and discuss the currently available data and provide our recommendations on when a metastatic biopsy should be obtained.