Histamine Releasing Factor (HRF) also known as Translationally Controlled Tumor Protein (TCTP) is a ubiquitous, novel protein that has both intracellular and extracellular functions. The purpose of this review is to highlight the background history of the molecule, the clinical implications and focus on the extracellular functions. Specifically the cells and the cytokines that are produced when stimulated by HRF/TCTP will be delineated as well as the signal transduction pathway that HRF/TCTP elicits will be described. Originally it was thought that HRF/TCTP interacted with IgE. Subsequently, cells that do not bind IgE also respond to HRF/TCTP and the interaction with IgE was questioned. Now, very recently, HRF/TCTP or at least its mouse counterpart appears to interact with some, but not all IgE and IgG molecules. HRF/TCTP has been shown to activate multiple human cells including basophils, eosinophils, T cells and B cells. Many of the cells that are activated by HRF/TCTP participate in the allergic response, leading to the conclusion that the extracellular functions of HRF/TCTP could exacerbate the allergic, inflammatory response.