The treatment of inflammatory breast cancer (IBC) has been hampered by the diagnostic rarity of the disease and its consequent inclusion in clinical trials of preoperative treatment for the more indolent locally advanced breast cancer (LABC). Patients with IBC have a 2-fold greater probability of dying of their disease compared with patients diagnosed with LABC. The aggressive clinical portrait of IBC supports the recent investigative focus on determining molecular changes specific to IBC and developing novel systemic therapies that will favorably affect its poor disease prognosis. A significant amount of laboratory research has been involved in defining a specific "inflammatory signature" for IBC, denoting molecular changes consistently found in IBC. This work has involved human IBC tissue and cell lines and has demonstrated overexpression of several molecules governing metastatic dissemination, such as overexpression of E-cadherin concurrent with a dysfunctional mucin 1. An increased prevalence of mutant TP53, overexpression of RhoC, and vascular endothelial growth factor-A has been found to contribute to the dominant influence of angiogenesis in this disease. A greater understanding of the molecular mechanisms governing the pathophysiology of IBC has led to the development and clinical application of novel targeting agents for preoperative therapy. This study reviews the advances in molecular understanding of IBC and focuses on the efficacy of therapies that target the epidermal growth factor pathway and angiogenesis as well as early investigational therapies involving RhoC and TP53.