The greater use of screening has changed the stage distribution of breast cancer, and an increasing number of patients are diagnosed with earlier stages of the disease. Still, locally advanced breast cancer (LABC) remains a major clinical problem in the United States and a common presentation in many parts of the world. There is no standard definition of LABC. One commonly used includes patients with large primary tumors greater than 5 cm (T3) or with skin/chest wall involvement (T4), and/or fixed axillary (N2) or ipsilateral internal mammary (N3) lymph node involvement. According to the tumor node metastasis staging, these usually include stage IIIa (T0-2N2 or T3N1-2) and stage IIIb (T4Nx or TxN3) disease. Inflammatory breast cancer (T4d) is included in most classifications despite its distinct clinical behavior and worse prognosis overall, but it serves as an example of combined modality intervention. Historically, the term LABC has been applied to those clinical presentations where the disease is considered inoperable. However, these therapeutic principles (including preoperative or primary systemic therapy [PST]) are increasingly being applied to patients presenting with tumors greater than 5 cm and negative lymph nodes (stage IIb-T3N0) or even smaller tumors, who are considered to have operable disease and a better outcome than those traditionally classified as having LABC. PST is increasingly being used in otherwise operable stage I and II patients aiming at greater rates of breast conservation and earlier efficacy assessment. This article reviews many of these issues and ongoing research questions.