The choice of the most appropriate systemic treatment of patients with metastatic breast carcinoma is a multifaceted decision-making process. The role for the pathologist is to provide a definite diagnosis of metastatic breast carcinoma, whenever needed, and especially to assess the biological parameters with prognostic and predictive value. Although the vast majority of breast carcinomas maintain the same biological features both in the primary and in the metastases, some undergo changes that may indicate that a targeted systemic treatment should be stopped or started, be it endocrine or anti-HER2. Unfortunately these tumours cannot be easily identified clinically, and it may be useful to biopsy the metastatic sites for reassessment of the biological characteristic of the tumours. Intra-tumoural heterogeneity and clonal selection due to the therapy could explain changes in biological features during tumour progression, but it should also be taken into account that the available assays for evaluating hormone receptor and HER2 status are not 100% accurate, even in the hands of expert pathologists. To minimize the risk of inducing inappropriate changes in systemic treatments due to false-positive or false-negative results, the pathologists should make all efforts to improve accuracy and reproducibility of the assay procedures.