Breast and axillary lymph node specimens from breast cancer patients treated with neoadjuvant systemic therapy are being encountered by pathologists with increasing frequency. Evaluation of these specimens presents challenges that differ from those encountered during the examination of other types of breast specimens. This article reviews the key issues regarding the gross and microscopic evaluation of post-neoadjuvant systemic therapy breast and lymph node specimens, and emphasizes the importance of accurate specimen evaluation in assessing treatment response.