This article reviews the characteristics of high affinity IgE receptors (FcepsilonRI) and their role in the response to allergenic proteins. The requirements for successful cross-linking of FcepsilonRI on basophils and mast cells and subsequent degranulation by allergenic proteins will be explained in detail. Methods for in vitro analysis of allergen-induced mast cell and basophil degranulation will be described and issues/problems in applying these methods will be discussed. Finally, implications for manipulation of protein allergens will be discussed.