Inflammatory breast cancer (IBC) is the most aggressive form of breast cancer. Despite extensive study, whether inflammation contributes to the tumorigenicity or aggressiveness of IBC remains largely unknown. In this chapter, we will review the potential role played by inflammation in IBC based on the results of in vitro, in vivo, and patient studies. Current evidence suggests that several major inflammatory signaling pathways are constitutively active in IBC and breast cancer. Among them, the NF-κB, COX-2, and JAK/STAT signaling systems seem to play a major role in the tumorigenesis of IBC. Inflammatory molecules such as interleukin-6, tumor necrosis factor alpha (TNF-α), and gamma interferon have been shown to contribute to malignant transformation in preclinical studies of IBC, while transforming growth factor-β, interleukins 8 and 1β, as well as TNF-α appear to play a role in proliferation, survival, epithelial–mesenchymal transition, invasion, and metastasis. In this chapter, we also describe work thus far involving inhibitors of inflammation in the development of prevention and treatment strategies for IBC.