Accurate pathological diagnosis of tumor mass before treatment and careful examination of specimens after treatment are two main objectives in the diagnostic process of neoadjuvant-treated breast cancer. To achieve the first objective, multiple core biopsies can be taken to assess intratumor heterogeneity and thus to address a more targeted therapeutic protocol. At the same time, fine needle aspiration cytology of lymph nodes found suspicious at ultrasound examination may be useful to plan surgical treatment. As for the second objective, a careful examination of specimens after primary systemic therapy is mandatory to evaluate the effect of treatment. In fact, clinical response does not necessarily correlate with pathological response. Pathological complete response (no residual invasive tumor, in situ carcinoma can be present, and no residual lymph node metastasis) constitutes an independent predictor of outcome in neoadjuvant-treated patients. Residual isolated tumor cells in primary tumor and in lymph nodes do not affect patient outcome.