Preoperative systemic therapy is the standard of care in locally advanced breast cancer. In this setting, the intent of preoperative systemic therapy is to expand surgical options and to improve survival. Locally advanced and inflammatory breast cancer have different biological features, but they share the use of preoperative (primary, neoadjuvant) systemic therapy as the initial treatment of choice. The management of these patients necessitates involvement of a multidisciplinary team from the onset and during therapy. The eradication of invasive cancer from the breast and axillary lymph nodes, pathologic complete response, is a predictor of outcome associated with improved disease-free and overall survival. However, conventional chemotherapy regimens result in pathologic complete response in only a minority of patients. The management of patients with residual invasive disease after preoperative therapy is a common clinical problem for which additional research is necessary. The differential expression of genes and pathways in locally advanced and inflammatory breast cancer allows for the exploitation of targeted therapy, and early trials have shown exciting target and tumor effects. Much work remains, and future trials combining targeted and conventional therapies based on molecular subtypes and/or specific targets are needed if we hope to improve survival for patients with locally advanced breast cancer.