Several recent reports have suggested that binding monomeric IgE (mIgE) to its type 1 receptor, FcεRI, on mast cells induces important responses. These observations contradict the notion that it is the aggregation of this receptor that is essential for initiating mast cell response. In the present study, we suggest that the most probable causes for the reported observations are the experimental protocol used combined with the high expression levels of the FcεRI by mast cells. Specifically, we suggest using the published data and physicochemical calculations that the exceptionally high number of cell surface FcεRI-bound monoclonal IgE yields, in the two-dimensions of the cells’ membranes, a situation where even a low affinity of these mIgE for epitopes on their own structure or on another cell surface component may lead to their aggregation. Hence, we hypothesize that the reported response to mIgE binding is a result of such an FcεRI-IgE induced aggregation.