Most of the current therapies for the treatment of atopic diseases are based on drugs that inhibit or suppress components of the allergic inflammatory response. Antihistamines, bronchodilators, antiallergic drugs and corticosteroids remain by far the most effective therapeutic response to allergic diseases in reducing symptoms and concomitant inflammatory reactions. The last two decades witnessed a large number of works aimed at identifying medications targeting specific steps in the allergic cascade. Because the binding of IgE to mast cells via the high affinity surface mast cell receptor (FcεRI) is the central event in allergic manifestations, its inhibition seems the best approach for designing innovative antiallergic drugs. Progress has been made on the molecular level by using anti-IgE and anti-FcεRI antibodies, or chimeric proteins targeting Fc receptors. Nevertheless, validation of IgE and FcεRI as crucial targets for allergic disorders is provided by a wealth of studies where the antiallergic activity of small molecules, such as peptides, able to inhibit IgE/FcεRI interaction, was assessed. D-PAM, a tetrameric IgE-binding tripeptide, derived through combinatorial chemistry, represents a new and innovative mechanism for atopy treatment. Due to its polycationic structure, this peptide is active in in vitro (β- hexosaminidase release) and in vivo (passive and active cutaneous anaphylaxis) models of allergy, without interfering with IgE/FcεRI or IgE/Ag interaction, thus opening the way to development of new antiallergic drugs.