Since basophils appear to play a fundamental role in the maintenance of allergic inflammation, the factors involved in basophil activation have become a focus of investigation in many laboratories. From this interest, the field of histamine-releasing factors (HRFs) has evolved. Our laboratory reported that a factor was present in late-phase skin blister fluids that caused basophil histamine release. It was hypothesized that basophil degranulation in these donors was mediated by the interaction of these HRFs with a certain kind of IgE, and upon experimentation a functional heterogeneity of the IgE molecule was uncovered. We designated the IgE from HRF responders as IgE+; the remaining IgE molecules designated were IgE-. Initially, it was thought that HrHRF might exert its activity by directly interacting with IgE+; however, a number of recent experiments have questioned this hypothesis. Observations suggest, in part, that HrHRF mediates biological activities on inflammatory cells by binding to a specific receptor rather than to the IgE molecule and/or the FcepsilonRI. In parallel with the search for an HrHRF receptor, a number of experiments have been performed to determine whether mediator release by this protein proceeds via a signal transduction pathway other than the one triggered by classic IgE-dependent stimuli such as anti-IgE antibody or antigen. Although further characterization is ongoing, the evidence thus far is consistent with the concept that HRF may be an important regulator of the cellular inflammation involved in the pathophysiology of allergy.