Preoperative systemic (neoadjuvant) chemotherapy is both routine therapeutic modality for locally advanced breast cancer and a translational research model to identify biomarkers that predict treatment response. It is imperative that pathologic response be strongly prognostic in order to optimize the clinical and scientific information that can be gained from neoadjuvant clinical trials. Dichotomization of response as pathologic complete response (pCR) or residual disease (RD) is overly simplistic for these objectives, particularly because residual disease (RD) after neoadjuvant treatment includes a broad range of actual responses from near-pCR to frank resistance. More effective or prolonged neoadjuvant treatments should reduce the extent of RD in many patients, possibly blurring the prognostic distinction between pCR and RD. On the other hand, it should be possible to identify patients with resistant disease in order to develop predictive tests for this adverse outcome. Our research group recently proposed to measure residual cancer burden (RCB) as a continuous variable derived from the primary tumor dimensions, cellularity of the tumor bed, and axillary nodal burden. Each component contributes meaningful pathologic information and can be obtained using routine pathologic materials and methods of interpretation that could easily be implemented in routine diagnostic practice.