While locally advanced breast cancer (LABC) represents a small fraction of patients with breast cancer in industrialized nations, in developing countries it might constitute up to 50% of incident cases. The definition includes patients with stage IIB, III, and some with limited stage IV breast cancer. Inflammatory breast cancer (IBC) is part of LABC, but it is often reported separately, because of its dismal prognosis. LABC can be considered technically operable (stage II and IIIA), or inoperable (stage IIIB, IV and IBC). For the last two decades, patients with inoperable LABC and IBC have been treated with increasing frequency with systemic therapy first, followed by regional therapy, either surgical resection or radiotherapy. Most treatment programs also included adjuvant systemic therapy. The majority of patients with LABC and IBC respond to primary chemotherapy, and most can be rendered disease-free initially. Local control rates exceed 80% with modern combined-modality treatment strategies. Since most tumors are downstaged, some patients can be treated with breast-conserving treatments. The optimal sequence of local and systemic treatments has not been defined. Combined-modality therapies improve the treatment and the outcome for patients with LABC. Whether the sequence of utilization of various treatments influences outcome remains to be established. The administration of systemic therapies first also provides a useful biological model to assess the effects of systemic treatments on the primary tumor and regional metastases, since these are available for serial non-invasive evaluation and sampling of tumor tissue.